Novel chroman derivatives having estrogen receptor decomposition activity and uses thereof

Abstract

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of cancer and related diseases and conditions. Also provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 947,213, filed December 12, 2019, the entirety of which is incorporated herein by reference.

[0002] Field of the Disclosure The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of diseases and conditions, such as cancer. [Background technology]

[0003] Background of the disclosure Estrogens are female sex hormones that mediate a wide range of physiological processes (e.g., development of the female reproductive system, maintenance of bone mass, and protection of cardiovascular tissue and the central nervous system) by binding to their cognate estrogen receptors, ERα and ERβ. Upon binding of estrogen to the estrogen receptor ("ER"), the receptor undergoes a conformational change to homodimerize. The ER homodimers then bind to estrogen response elements ("ERE") present in the promoters of a specific set of target genes and, in cooperation with transcriptional coregulators, control the expression of the target genes. Thousands of canonical ER target genes have been identified, many of which control cell proliferation and survival.

[0004] Because ER signaling is involved in many pathways, it is well known that deregulation of ER signaling, particularly via ERα, can lead to uncontrolled cell proliferation and ultimately cancer. ER+ breast cancers account for approximately 75% of all diagnosed breast cancers, as well as some ovarian and endometrial cancers. The prevalence of ER+ cancers has led to decades of investigation and the development of antiestrogens as therapeutic agents.

[0005] Anti-estrogen (i.e., hormonal) therapy is the first choice of treatment for most ER+ breast cancers. There are three main classes of anti-estrogen therapeutics, including aromatase inhibitors (e.g., letrozole and anastrozole); selective estrogen modulating agents (e.g., tamoxifen, toremifene, and raloxifene); and selective estrogen receptor degraders (e.g., fulvestrant). These classes of anti-estrogen therapeutics act by different mechanisms of action, such as inhibition of the aromatase enzyme, competition for binding to ERα, and / or degradation of ERα.

[0006] The above-mentioned treatment may cause adverse effects.For example, the administration of aromatase inhibitors may cause bone mineral density to decrease, which may increase the risk of fracture.The administration of selective estrogen regulators may cause the development of endometrial cancer and / or the development of cardiovascular tissue (e.g., deep thrombosis and pulmonary embolism).In addition, the above-mentioned treatment may have poor clinical efficacy.

[0007] Therefore, there is a need to treat ER+ cancer without causing the known harmful side effects of current treatments.One approach to achieve this goal would be to utilize naturally occurring cellular ubiquitin-mediated degradation.Without being bound by any theory, it is believed that ERα degradation can occur when both ERα and ubiquitin ligase are bound and in close proximity.

[0008] Cereblon ("CRBN") E3 ubiquitin ligase is a ubiquitin ligase in which CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 and cullin 4. Cereblon E3 ubiquitin ligase functions as a substrate receptor by bringing substrates into close proximity for ubiquitination and subsequent degradation by the proteasome. Recently, it has been discovered that small molecule drugs, such as thalidomide and its closely related analogues lenalidomide and pomalidomide, can simultaneously interact with CRBN and several other proteins. By doing so, CRBN can be utilized for targeted protein degradation, such as IKZF1 and IKZF3. This is believed to explain the anti-myeloma effects of thalidomide and related compounds. Summary of the Invention [Means for solving the problem]

[0009] Disclosure Summary In some embodiments, the compound of formula (I): [ka] Provided herein is a stereoisomer or mixture of stereoisomers, or a pharma- ceutically acceptable salt, or hydrate thereof, During the ceremony, R 1 is selected from H, C1-C6 acyl, or C1-C6 alkyl, each of which is selected from 0, 1, 2, or 3 R 6 is replaced by; R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 is replaced by; Each R 4 is independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6or two R 4 The groups together form oxo; R 5 teeth, hydrogen, Halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2, and -CN, each of which is selected from 0, 1, 2, or 3 R 6 is replaced by; X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 is replaced by; X 3 and X 4 are each independently selected from H or halo; L is a linker 1-22 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 6 is replaced by; Each R 6 is independently selected from C1-C6 alkyl, halo, cyano, and hydroxy; Each R 7 are independently selected from hydrogen, C1-C6 alkyl, and acyl, each of which may be represented by 0, 1, 2, or 3 R 6 or two R 7 The groups taken together form a 3- to 6-membered heterocycle or heteroaryl.

[0010] In some embodiments, the compound of formula (I) may include both cis and trans isomers. In some embodiments, the compound of formula (I) may be a mixture of cis and trans isomers. In some embodiments, the compound of formula (I) may be a cis isomer.

[0011] In some embodiments, the compound of formula (I) may include both stereoisomers and mixtures of stereoisomers. In some embodiments, the compound of formula (I) is a stereoisomer. In some embodiments, the compound of formula (I) may include both racemic isomers and enantiomers.

[0012] In some embodiments, formula (I) * Compounds of: [ka] is provided herein.

[0013] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, in some embodiments, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. [Brief description of the drawings]

[0014] BRIEF DESCRIPTION OF THE DRAWINGS The foregoing summary as well as the following detailed description of the present disclosure will be better understood when read in conjunction with the accompanying drawings. For the purposes of illustrating the present disclosure, the accompanying drawings illustrate some, but not all, alternative embodiments. It should be understood, however, that the present disclosure is not limited to the precise arrangements and instrumentalities shown. These drawings, which are incorporated in and constitute a part of the specification, serve to explain the principles of the present disclosure.

[0015] [Figure 1A]1A-1D show the ERα degradation activity of exemplary compounds of the present disclosure, 85, 60, 32, and 52, in the T47D cell line 6 hours after administration. [Figure 1B] 1A-1D show the ERα degradation activity of exemplary compounds of the present disclosure, 85, 60, 32, and 52, in the T47D cell line 6 hours after administration. [Figure 1C] 1A-1D show the ERα degradation activity of exemplary compounds of the present disclosure, 85, 60, 32, and 52, in the T47D cell line 6 hours after administration. [Figure 1D] 1A-1D show the ERα degradation activity of exemplary compounds of the present disclosure, 85, 60, 32, and 52, in the T47D cell line 6 hours after administration.

[0016] [Figure 2A] 2A and 2B show the ERα degradation activity of exemplary compounds of the present disclosure, 87 and 84, in the T47D cell line 6 hours after administration. [Figure 2B] 2A and 2B show the ERα degradation activity of exemplary compounds of the present disclosure, 87 and 84, in the T47D cell line 6 hours after administration.

[0017] [Figure 3A] 3A and 3B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in MCF7 cell lines 6 hours after administration. [Figure 3B] 3A and 3B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in MCF7 cell lines 6 hours after administration.

[0018] [Figure 4A] 4A and 4B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in the T47D cell line 6 hours after administration. [Figure 4B] 4A and 4B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in the T47D cell line 6 hours after administration.

[0019] [Figure 5A] 5A and 5B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in the CAMA-1 cell line 6 hours after administration. [Figure 5B] 5A and 5B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in the CAMA-1 cell line 6 hours after administration.

[0020] [Figure 6A] 6A, 6B, and 6C show the ERα degradation activity of exemplary compounds of the present disclosure, 41, 42, and 63, in the T47D cell line 6 hours after administration. [Figure 6B] 6A, 6B, and 6C show the ERα degradation activity of exemplary compounds of the present disclosure, 41, 42, and 63, in the T47D cell line 6 hours after administration. [Figure 6C] 6A, 6B, and 6C show the ERα degradation activity of exemplary compounds of the present disclosure, 41, 42, and 63, in the T47D cell line 6 hours after administration.

[0021] [Figure 7A] 7A, 7B, 7C, and 7D show the ERα degradation activity of exemplary compounds of the present disclosure, 89, 56, 90, and 74, in the T47D cell line 6 hours after administration. [Figure 7B] 7A, 7B, 7C, and 7D show the ERα degradation activity of exemplary compounds of the present disclosure, 89, 56, 90, and 74, in the T47D cell line 6 hours after administration. [Figure 7C] 7A, 7B, 7C, and 7D show the ERα degradation activity of exemplary compounds of the present disclosure, 89, 56, 90, and 74, in the T47D cell line 6 hours after administration. [Figure 7D] 7A, 7B, 7C, and 7D show the ERα degradation activity of exemplary compounds of the present disclosure, 89, 56, 90, and 74, in the T47D cell line 6 hours after administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description Definitions As used herein, "cancer" refers to diseases, disorders and conditions involving abnormal cell growth that has the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0023] "Subject" refers to an animal, e.g., a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

[0024] As used herein, "treatment" or "treating" refers to the improvement of a disease or disorder or at least one discernible symptom thereof. In another embodiment, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to the inhibition of the progression of a disease or disorder, either physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treatment" or "treating" refers to the delay of the onset of a disease or disorder. For example, the treatment of a cholesterol disorder may include lowering blood cholesterol levels.

[0025] As used herein, "prevention" or "preventing" refers to a reduction in the risk of acquiring a given disease or disorder.

[0026] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of the substituent. For example, -CN is attached through a carbon atom.

[0027] "Optionally" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes the cases where the event or circumstance occurs and the cases where they do not occur. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined below. Those skilled in the art will understand that with respect to groups containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or inherently unstable.

[0028] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C81, C79, C82, C79, C93, C94, C95, C96, C97, C98, C99, C99, C101, C102, C103, C104, C105, C106, C107, C108, C109, C110, C111, C112, C113, C114, C115, C116, C117, C118, C119, C121, C122, C123, C124, C125, C135, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 Alkyl is intended to be included.

[0029] As used herein, the term "acyl" refers to a RC(O)- group (including, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-), where the foregoing groups are attached to the parent molecular structure through a carbonyl functionality. In some embodiments, acyl is a C 1~10An acyl group, which refers to the total number of chain or ring atoms of, for example, an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety and the carbonyl carbon of the acyl. For example, a C4-acyl has three other ring or chain atoms and the carbonyl.

[0030] The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond, such as straight or branched groups of 2 to 8 carbon atoms, referred to herein as (C2-C8) alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0031] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as (C1-C8) alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, the "alkyl" is a straight chain hydrocarbon. In some embodiments, an "alkyl" is a branched chain hydrocarbon.

[0032] The term "alkynyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, such as straight or branched groups of 2 to 8 carbon atoms, referred to herein as (C2-C8)alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0033] As used herein, the term "aryl" refers to a carbomonocyclic, carbobicyclic or other carbopolycyclic aromatic ring system having 5 to 14 ring atoms. The aryl group may be optionally fused to one or more rings selected from aryl, cycloalkyl, heteroaryl and heterocyclyl. The aryl groups of the present disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups include, but are not limited to, monocyclic aromatic ring systems in which the ring contains 6 carbon atoms, referred to herein as "C6-aryl."

[0034] The term "cyano" as used herein refers to --CN.

[0035] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group of 3 to 16 carbons or 3 to 8 carbons (referred to herein as "(C3-C8)cycloalkyl") derived from a cycloalkane. Exemplary cycloalkyls include, but are not limited to, cyclohexane, cyclohexene, cyclopentane and cyclopentene. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups may be fused to other cycloalkyl groups (saturated or partially unsaturated), aryl groups or heterocyclyl groups to form bicyclic, tetracyclic, etc. rings. The term "cycloalkyl" also includes bridged and spiro-fused ring structures, which may or may not contain heteroatoms.

[0036] As used herein, the term "halo" or "halogen" refers to -F, -Cl, -Br and / or -I.

[0037] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or other polycyclic aromatic ring system containing one or more heteroatoms, such as 1-4 heteroatoms, such as nitrogen, oxygen and sulfur. Heteroaryls may be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls may also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidylyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, referred to herein as "(C2-C5)heteroaryl," in which the ring contains 2 to 5 carbon atoms and 1 to 3 heteroatoms.

[0038] As used herein, the terms "heterocycle", "heterocyclyl" or "heterocyclic" refer to a saturated or unsaturated 3-18 membered ring containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, respectively. Heterocycles can be aromatic (heteroaryl) or non-aromatic. Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic and tetracyclic groups in which any of the above heterocycles are fused to one or two rings independently selected from aryl, cycloalkyl and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, Examples include oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl.

[0039] As used herein, the terms "hydroxy" and "hydroxyl" refer to --OH.

[0040] As used herein, the term "pharmaceutical acceptable carrier" refers to any and all solvents, dispersion media, coating agents, isotonic agents, absorption retardants, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional or enhanced therapeutic functions.

[0041] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0042] The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of the present disclosure that is within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, effective for the intended use, and, where possible, a zwitterionic form of the compound of the present disclosure. Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14 and Roche, EB, ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (both of which are incorporated herein by reference).

[0043] The term "pharmacologically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds included in the compositions of the present invention that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharma-ceutically acceptable acid addition salts of such basic compounds include non-toxic acid addition salts (i.e., salts containing pharmacologically acceptable anions, such as sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, hydrophosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, etc. The acids that form salts include, but are not limited to, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds contained in the compositions of the present invention that contain amino moieties can form pharma- ceutically acceptable salts with various amino acids in addition to the acids listed above. Compounds contained in the compositions of the present invention that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0044] Chemical names were generated using PerkinElmer ChemDraw® Professional, version 17.

[0045] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, e.g., geometric isomers, enantiomers or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers or diastereomers. These compounds may be represented by the symbols "R" or "S" depending on the configuration of the substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be represented by "(±)" in terms of nomenclature, although one of ordinary skill in the art will recognize that the structure may exhibit chiral centers. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0046] In some embodiments, the compounds are racemic mixtures of (S)- and (R)-isomers. In other embodiments, mixtures of compounds are provided herein in which the individual compounds of the mixture are predominantly present in the (S)- or (R)-isomeric configuration. For example, the mixtures of compounds have an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the mixture of compounds has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or higher. In other embodiments, the mixture of compounds has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the mixture of compounds has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or higher.

[0047] Individual stereoisomers of the compounds of the present disclosure can be prepared by synthesis from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) combining the resulting diastereomeric mixture with a chiral auxiliary, recrystallizing or chromatographically separating the enantiomeric mixture, and separating the optically pure product from the auxiliary, (2) salt formation with an optically active resolving agent, or (3) directly separating the mixture of optical enantiomers by a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0048] Geometric isomers may also exist in the compounds of the present disclosure.The present disclosure encompasses various geometric isomers and their mixtures resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring.Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards.Unless otherwise specified, structures depicting double bonds encompass both E and Z isomers.

[0049] Alternatively, substituents around a carbon-carbon double bond may be designated "cis" or "trans", with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans". The term "cis" represents substituents on the same face of the ring and the term "trans" represents substituents on opposite faces of the ring. A mixture of compounds in which substituents are located both on the same side and on opposite faces of the ring is designated as "cis / trans".

[0050] The compounds disclosed herein can exist as tautomers, and both tautomeric forms are intended to be encompassed by the scope of the disclosure even though only one tautomeric structure is shown.

[0051] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, deuterium ( 2 H) or tritium ( 3 H) by replacement of hydrogen, or 13 C- or 14 Compounds having this structure, except for the replacement of a carbon with a C-carbon atom, are within the scope of this disclosure. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or therapeutic agents. compound In some embodiments, the compound of formula (I): [ka] Provided herein is a stereoisomer or mixture of stereoisomers, a pharma- ceutically acceptable salt, or a hydrate thereof, During the ceremony, R 1 is selected from H, C1-C6 acyl, or C1-C6 alkyl, each of which is selected from 0, 1, 2, or 3 R 6 is replaced by; R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 is replaced by; Each R 4 is independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 or two R 4 The groups together form oxo; R 5 teeth, hydrogen, Halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2, and -CN, each of which is selected from 0, 1, 2, or 3 R 6 is replaced by; X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 is replaced by; X 3 and X 4 are each independently selected from H or halo; L is a linker 1-22 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 6 is replaced by; Each R 6 is independently selected from C1-C6 alkyl, halo, cyano, and hydroxy; Each R 7 are independently selected from hydrogen, C1-C6 alkyl, and acyl, each of which may be represented by 0, 1, 2, or 3 R 6 or two R 7 The groups taken together form a 3- to 6-membered heterocycle or heteroaryl.

[0052] In some embodiments, R 1 is selected from H, or C1-C6 alkyl, each of which is selected from 0, 1, 2 or 3 R 6 In some embodiments, R 1may be selected from H or methyl, each of which may be selected from 0, 1, 2 or 3 R 6 In some embodiments, R 1 may each independently be H or methyl.

[0053] In some embodiments, R 1 can be H. In some embodiments, R 1 can be methyl.

[0054] In some embodiments, R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 In some embodiments, R 2 and R 3 are each independently selected from H and methyl, each of which is selected from 0, 1, 2 or 3 R 6 In some embodiments, R 2 and R 3 are each independently selected from H and methyl.

[0055] In some embodiments, R 2 can be H, R 3 can be H. In some embodiments, R 2 can be H, R 3 can be methyl. In some embodiments, R 2 can be methyl, R 3 can be H. In some embodiments, R 2 can be methyl, R 3 can be methyl.

[0056] In some embodiments, each R 4 is independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R6 or two R 4 The groups taken together form oxo. In some embodiments, each R 4 are independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl, or two R 4 The groups taken together form oxo. In some embodiments, R 4 is H. In some embodiments, two R 4 The groups taken together form oxo.

[0057] In some embodiments, R 5 teeth, hydrogen, Halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2, and -CN, each of which is selected from 0, 1, 2, or 3 R 6 In some embodiments, R 5 teeth, hydrogen, Halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 In some embodiments, R 5 is selected from halogen. In some embodiments, R 5 can be F.

[0058] In some embodiments, X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, each of which may be present in the presence of 0, 1, 2, or 3 R 6 In some embodiments, X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.1 and X 2 are each independently selected from H, F, CN, methyl, methoxy, and trifluoromethyl.

[0059] In some embodiments, X 1 is H and X 2 is H. In some embodiments, X 1 is F and X 2 is F. In some embodiments, X 1 is H and X 2 is methyl. In some embodiments, X 1 is methyl and X 2 is H. In some embodiments, X 1 is H and X 2 is F. In some embodiments, X 1 is F and X 2 is H. In some embodiments, X 1 is H and X 2 is methoxy. In some embodiments, X 1 is methoxy and X 2 is H. In some embodiments, X 1 is F and X 2 is methyl. In some embodiments, X 1 is methyl and X 2 is F. In some embodiments, X 1 is F and X 2 is methoxy. In some embodiments, X 1 is methoxy and X 2 is F. In some embodiments, X 1 is F and X 2 is trifluoromethyl. In some embodiments, X 1 is trifluoromethyl, and X 2 is F.

[0060] In some embodiments, X 3 and X 4 are each independently selected from H or halo.3 and X 4 are each independently selected from H or F.

[0061] In some embodiments, X 3 is H and X 4 is H. In some embodiments, X 3 is F and X 4 is F. In some embodiments, X 3 is H and X 4 is F. In some embodiments, X 3 is F and X 4 is H.

[0062] In some embodiments, L can be a linker of 1-22 carbon atoms in length, where one or more of the carbon atoms is C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker of 1-20 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker of 1-18 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5In some embodiments, L can be a linker of 1-16 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker 1-14 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker 1-12 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker of 1-10 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 are independently substituted with

[0063] In some embodiments, L can be a linker of 1-8 carbon atoms in length, where one or more of the carbon atoms is C(O), O, NR 4, S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker of 1-6 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker 1-4 carbon atoms in length, where one or more of the carbon atoms is a C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally independently replaced by 0, 1, 2, or 3 R 5 are independently substituted with

[0064] In some embodiments, L can be a linker in which two carbon atoms are each independently replaced by a heterocycle, each of which is selected from 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker, in which one carbon atom is replaced by a heterocycle and one carbon atom is replaced by a cycloalkyl, each of which is independently substituted with 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker, where more than one carbon atom is independently substituted with C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is independently replaced by 0, 1, 2, or 3 R 5In some embodiments, L can be a linker, where more than one carbon atom is substituted with C(O), O, and NR 4 each of which is independently substituted by a group selected from 0, 1, 2 or 3 R 5 has been replaced with.

[0065] In some embodiments, L is [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] In some embodiments, L can be: [ka] It could be.

[0066] In some embodiments, the compound of formula (I) is a cis isomer.

[0067] In some embodiments, the compounds of formula (I) are stereoisomers.

[0068] In some embodiments, formula (I) * Compounds of: [ka] is provided herein.

[0069] In some embodiments, provided herein is a compound selected from the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] Pharmaceutical Compositions

[0070] The pharmaceutical compositions of the present disclosure comprise at least one compound of formula (I), its tautomer, stereoisomer, pharma-ceutically acceptable salt, or hydrate, formulated with one or more pharma-ceutically acceptable carriers.These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration.The most suitable administration form in any given case will depend on the extent and severity of the condition to be treated and the nature of the particular compound used.

[0071] Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each of which contains a predetermined amount of the disclosed compound as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy, including combining at least one compound of the present invention as an active compound with a carrier or excipient, which may constitute one or more accessory ingredients. The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. The carrier may be solid or liquid, or both, and may be formulated with at least one compound described herein as an active compound in a unit dose formulation, such as a tablet, which may contain about 0.05% to about 95% by weight of at least one active compound. Other pharmacologically active substances, including other compounds, may also be present. The formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy which consist essentially of admixing the ingredients.

[0072] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Pharmacologically administrable liquid compositions can be prepared, for example, by dissolving or dispersing at least one active compound of the present disclosure described herein and optional pharmaceutical adjuvants in an excipient, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming a solution or suspension. In general, suitable formulations can be prepared by uniformly and intimately mixing at least one active compound of the present disclosure with a liquid or finely divided solid carrier or both, and then, if necessary, shaping the product. For example, tablets can be prepared by compressing or shaping a powder or granules of at least one compound of the present disclosure, which can be combined with one or more accessory ingredients if necessary. Compressed tablets may be prepared by compressing in a suitable machine at least one compound of the present disclosure in a free-flowing form, e.g., powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant(s). Molded tablets may be made by molding in a suitable machine at least one compound of the present disclosure in powder form moistened with an inert liquid diluent.

[0073] Formulations suitable for buccal (sublingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, as well as lozenges comprising at least one compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

[0074] Formulations of the present disclosure suitable for parenteral administration include sterile aqueous preparations of at least one of Formula (I), or tautomers, stereoisomers, pharma- ceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be accomplished by subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by mixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with blood. Injectable compositions of the present disclosure may contain from about 0.1 to about 5% w / w of the active compound.

[0075] Formulations suitable for rectal administration are presented as unit dose suppositories. These can be prepared by mixing at least one compound described herein with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0076] Preparations suitable for topical application to the skin may take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers and excipients that can be used include petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more thereof. The active compound (i.e., at least one of formula (I), or its tautomers, stereoisomers, pharma-ceutically acceptable salts, and hydrates) is generally present at a concentration of about 0.1% to about 15% w / w of the composition, for example, about 0.5 to about 2%.

[0077] The amount of active compound administered will depend on the subject being treated, the subject's weight, the mode of administration, and the judgment of the prescribing physician. For example, the administration schedule may involve once-daily or twice-daily administration of the encapsulated compound at an approved dosage of about 1 μg to about 1000 mg. In another embodiment, intermittent administration of doses of the encapsulated compound (e.g., monthly or yearly) may be used. Encapsulation allows for easy access to the site of action and allows for simultaneous administration of active ingredients, theoretically resulting in a synergistic effect. Following standard administration regimens, a physician will be able to easily determine the optimal dosage and easily modify the administration to achieve such dosage.

[0078] The therapeutically effective amount of the compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.However, dosage can vary according to the requirements of the patient, the severity of the condition to be treated, and the compound used.In one embodiment, the therapeutically effective amount of the disclosed compound is sufficient to achieve maximum plasma concentration.For example, the preliminary dose determined according to animal test, and the dosage scale for administration to humans are carried out according to art-accepted practices.

[0079] Toxicity and therapeutic efficacy can be measured, for example, by LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio of toxic to therapeutic effects can be determined by standard pharmaceutical procedures in cell cultures or experimental animals to determine the dose that is therapeutically effective in 50% of the population. The dose ratio of toxic to therapeutic effects is the therapeutic index, which is defined as the ratio LD 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0080] The data obtained from cell culture assays or animal studies can be used to formulate a range of dosages for use in humans.For use in other animals, including humans, the therapeutically effective dosage achieved in one animal model can be converted using conversion factors known in the art (see, for example, Freireich et al., Cancer Chemother.Reports 50(4):219-244(1966) and the following table for equivalent surface area dosage factors). [Table 2]

[0081] The dosage of such compounds is preferably 50 The circulating concentration range includes 0.1 to 0.5 mg / kg / day, with little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration used. In general, the therapeutically effective amount can vary with the age, condition and sex of the subject, as well as the severity of the medical condition in the subject. The dosage can be determined by a physician and adjusted as necessary to suit the observed treatment effect. Treatment Method

[0082] In some embodiments, a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered to treat cancer in a subject in need thereof. In some embodiments, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is ERα positive. In some embodiments, a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered as a pharmaceutical composition. In some embodiments, the subject has previously been treated with tamoxifen.

[0083] In some embodiments, the use of a compound of formula (I), or a tautomer, stereoisomer, pharma- ceutically acceptable salt, or hydrate thereof, in therapeutic treatment is provided herein. In some embodiments, the therapeutic treatment is for the treatment of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of breast cancer. In some embodiments, the therapeutic treatment is for lung cancer. In some embodiments, the therapeutic treatment is for the treatment of ovarian cancer. In some embodiments, the therapeutic treatment is for the treatment of endometrial cancer. In some embodiments, the therapeutic treatment is for the treatment of prostate cancer. In some embodiments, the therapeutic treatment is for the treatment of esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of estrogen-related diseases and conditions. In some embodiments, the therapeutic treatment is for the treatment of infertility. In some embodiments, the therapeutic treatment is for the treatment of ovulatory dysfunction. In some embodiments, the therapeutic treatment is for the treatment of postmenopausal osteoporosis. In some embodiments, the therapeutic treatment is for the treatment of estrogen-associated gynecomastia. In some embodiments, the therapeutic treatment is for the treatment of dyspareunia due to menopause. In some embodiments, the therapeutic treatment is for the treatment of retroperitoneal fibrosis. In some embodiments, the therapeutic treatment is for the treatment of idiopathic sclerosing mesenteritis.

[0084] In some embodiments, provided herein is the use of a compound of formula (I), or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate, in the preparation of a medicament.In some embodiments, provided herein is a method of inhibiting cell proliferation, comprising contacting a cell with a compound of formula (I), or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate.In some embodiments, the cell is a cancer cell.In some embodiments, the cell can express ERα.

[0085] In one embodiment, the compound of formula (I), or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate, can be administered in combination with another therapeutic agent. The other therapeutic agent can provide additive or synergistic value compared to administration of the compound of the present disclosure alone. The therapeutic agent can be selected from, for example, hormones and hormone analogs; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolite neoplastic agents; antibiotic neoplastic agents; alkylating agents; antimicrotubule agents; platinum coordination complexes; aromatase inhibitors; and antimitotic agents.

[0086] In some embodiments, the therapeutic agent can be a hormone or hormone analog. In some embodiments, the therapeutic agent can be a signal transduction pathway inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase I inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase II inhibitor. In some embodiments, the therapeutic agent can be an antimetabolite neoplastic agent. In some embodiments, the therapeutic agent can be an antibiotic neoplastic agent. In some embodiments, the therapeutic agent can be an alkylating agent. In some embodiments, the therapeutic agent can be an anti-microtubule agent. In some embodiments, the therapeutic agent can be a platinum coordination complex. In some embodiments, the therapeutic agent can be an aromatase inhibitor. In some embodiments, the therapeutic agent can be an anti-mitotic agent.

[0087] In some embodiments, the aromatase inhibitor may be selected from anastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane. In some embodiments, the aromatase inhibitor is anastrazole. In some embodiments, the aromatase inhibitor may be letrozole. In some embodiments, the aromatase inhibitor may be vorozole. In some embodiments, the aromatase inhibitor may be fadrozole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formestane.

[0088] In some embodiments, the antimitotic agent can be selected from paclitaxel, docetaxel, and abraxane. In some embodiments, the antimitotic agent can be paclitaxel. In some embodiments, the antimitotic agent can be docetaxel. In some embodiments, the antimitotic agent can be abraxane.

[0089] In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with a hormone or hormone analog. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with a signal transduction pathway inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with an antimetabolite neoplastic agent. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with a topoisomerase I inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with a topoisomerase II inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with an aromatase inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with one or more anti-cancer agents.

[0090] In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate may be administered in combination with an anticancer drug, and the anticancer drug is tamoxifen.In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate may be administered in combination with an anticancer drug, and the anticancer drug is fulvestrant. EXAMPLES

[0091] The examples and preparations provided below further illustrate and exemplify the compounds disclosed herein and methods of preparing such compounds. It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations.

[0092] Chemicals described herein may be synthesized according to one or more of the exemplary schemes herein and / or techniques known in the art. Unless otherwise specified, reactions described herein are carried out at atmospheric pressure, generally within a temperature range of about -10°C to about 200°C. Furthermore, unless otherwise specified, reaction times and conditions are approximate, e.g., carried out at about atmospheric pressure, within a temperature range of about -10°C to about 200°C, for a period that may be, e.g., about 1 to about 24 hours; in some embodiments, reactions that are allowed to proceed overnight may average a period of about 16 hours.

[0093] Isolation and purification of the chemicals and intermediates described herein can be carried out, if desired, by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, or a combination of these procedures. See, for example, Carey et al., Advanced Organic Chemistry, 3 rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2 nd Ed., 2005 Hoboken, NJ: J. Wiley & Sons. Specific illustrations of suitable separation and isolation procedures are given by reference to the examples below. However, other equivalent separation or isolation procedures may also be used.

[0094] In all methods, it is well understood that protecting groups for sensitive or reactive groups may be used where necessary in accordance with general chemical principles. Protecting groups are manipulated in accordance with standard organic synthesis methods (TW Greene and PG M Huts (1999) Protective Groups in Organic Synthesis, 3rd Edition, 1999). rdEd., John Wiley & Sons. These groups may be removed at any convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0095] If desired, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example, by the formation of diastereoisomeric salts or complexes that can be separated by crystallization; through the formation of diastereoisomeric derivatives that can be separated by, for example, crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic oxidation or reduction, followed by separation of the altered and unaltered enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with bound chiral ligands or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other in an asymmetric transformation.

[0096] The compounds described herein may be optionally contacted with a pharma- ceutically acceptable acid to form the corresponding acid addition salt, and the compounds described herein may be optionally contacted with a pharma- ceutically acceptable base to form the corresponding base addition salt.

[0097] In some embodiments, the disclosed compounds can be generally synthesized by appropriate combination of generally known synthetic methods.The techniques useful in synthesizing these chemical entities are easily apparent and accessible to those skilled in the relevant field based on this disclosure.Many of the starting compounds and other reactants that are optionally substituted are commercially available, for example, from Millipore Sigma, or can be easily prepared by those skilled in the art using commonly used synthetic methods.

[0098] The following discussion is provided to illustrate some of the various methods available for use in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that may be used in preparing the compounds provided herein. Those of skill in the art will understand that, unless otherwise specified, in the naming of genuses or compounds, standard valences apply to all compounds disclosed herein. The following abbreviations have the definitions given below: 1. BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 2. CbzCl: Benzyloxycarbonyl chloride 3. DCE: 1,2-dichloroethane 4. DCM: dichloromethane 5. DIEA or DIPEA: N,N-diisopropylethylamine 6. DMEM: Dulbecco's Modified Eagle Medium 7.DMSO: Dimethyl sulfoxide 8. DMF: N,N-Dimethylformamide 9. EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 10. ESI-TOF: Electrospray ionization time-of-flight mass spectrometry 11. EtOAc: Ethyl acetate 12.FBS: Fetal bovine serum 13.HOAt: 1-Hydroxy-7-azabenzotriazole 14. HPLC: High Pressure Liquid Chromatography 15.HRMS: High resolution mass spectrometry 16.IBX: 2-Iodoxybenzoic acid 17. MeOH: Methanol 18. MCF-7: Michigan Cancer Foundation-7 breast cancer cell line 19.MTBE: Methyl tert-butyl ether 20. NBS: N-bromosuccinimide 21.NMR: Nuclear magnetic resonance 22. NCS: N-chlorosuccinimide 23. Pd(dppf)Cl2: Bis(diphenylphosphino)ferrocene palladium dichloride 24. RPMI: Roswell Park Memorial Institute medium 25. SDS: Sodium dodecyl sulfate 26. SFC: Supercritical Fluid Chromatography 27. TBAB: Tetrabutylammonium bromide 28. TBST: Tris-buffered saline containing Tween 20 29.TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy 30. p-TSA or TsOH: p-Toluenesulfonic acid 31.THF: Tetrahydrofuran Example 1. Synthesis of compounds of the present disclosure.

[0099] General chemical procedures. HPLC spectra of all compounds were acquired using an Agilent 1200 series system equipped with a DAD detector. Chromatography was performed on a 2.1 x 150 mm Zorbax 300SB-C18 5 μm column with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.4 mL / min. The gradient program was as follows: 1% B (0-1 min), 1-99% B (1-4 min), and 99% B (4-8 min). High-resolution mass spectral (HRMS) data were acquired in positive ion mode using an Agilent G1969A API-TOF equipped with an electrospray ionization (ESI) ion source. Nuclear magnetic resonance (NMR) spectra were acquired on a Bruker spectrometer at 600 MHz or 400 MHz ( 1 1 H NMR) and 150 MHz for carbon ( 13 C NMR; chemical shifts are reported in (δ). Preparative HPLC was performed on an Agilent Prep 1200 series with UV detectors set at 254 nm and 220 nm. Samples were analyzed using a Phenomenex Luna 75×30 mm, 5 μm, C 18The column was injected at room temperature. The flow rate was 40 mL / min. A linear gradient was used from 10% (or 50%) MeOH (A) to 100% MeOH (B) in HO (containing 0.1% TFA). HPLC was used to establish the purity of the target compounds. All final compounds were determined to be >95% pure when analyzed according to the HPLC method described above.

[0100] The compounds having the structure of formula (I) claimed in the present application can be prepared by connecting two ligands by a linker. In general, the molecules claimed in the present application can be reached in a stepwise or modular manner. The following schemes represent the general methods used in preparing these compounds. However, the synthesis of formula (I) is not limited to these representative methods, since they can also be prepared by those skilled in the art of synthetic chemistry. Scheme 1: Synthesis of Compound 1 [ka] Scheme 2: Synthesis of compound 2 [ka] Scheme 3: Synthesis of compound 3 [ka] Scheme 4: Synthesis of compound 4 [ka] Scheme 5: Synthesis of compounds 5-8 [ka] Scheme 6: Synthesis of compounds 9-11 [ka] Scheme 7: Synthesis of compounds 12-25 [ka] [ka] Scheme 8: Synthesis of compounds 26, 28-31 [ka] Scheme 9: Synthesis of compound 27 [ka] Scheme 10: Synthesis of compounds 32-36 [ka] Scheme 11: Synthesis of compounds 37 and 44. [ka] Scheme 12: Synthesis of compounds 38–43, 45, 50–57, 60–65, 72–80, 84–87, and 89–90. [ka] Scheme 13: Synthesis of compounds 68-71. [ka]

[0101] The synthesis of compounds 46, 47, 48, 49, 58, 59, 66, 67, 81-83, and 88 can follow the schemes described in Schemes 8, 9, and 12. Example 1: Synthesis of cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (compound 36). [ka] [ka] Step 1: Preparation of (1-(4-bromophenyl)piperidin-4-yl)methanol.

[0102] To a mixture of 1-bromo-4-iodobenzene (100 g, 353 mmol, 1.00 equiv.) and piperidin-4-ylmethanol (52.8 g, 459 mmol, 1.30 equiv.) in DMSO (500 mL), cis-4-hydroxy-L-proline (9.22 g, 70.5 mmol, 0.200 equiv.), CuI (13.4 g, 70.5 mmol, 0.200 equiv.), and K3PO4 (150 g, 0.705 mol, 2.00 equiv.) were added. The mixture was stirred at 80° C. for 16 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.80, Rf(product)=0.30) showed that the starting material was completely consumed. The mixture was poured into ice water (2.50 L) and extracted with EtOAc (1.00 L×2). The organic layers were combined and washed with ammonium hydroxide solution (500 mL×3, 30 mL ammonium hydroxide in 210 mL H2O). The organic layers were washed with brine (500 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo to give (1-(4-bromophenyl)piperidin-4-yl)methanol as an off-white solid. Step 2: Preparation of 1-(4-bromophenyl)piperidine-4-carbaldehyde.

[0103] To a solution of (1-(4-bromophenyl)piperidin-4-yl)methanol (80.0 g, 296 mmol, 1.00 equiv.) in DMSO (220 mL) and DIPEA (193 g, 1.49 mol, 261 mL, 5.00 equiv.), pyridine·sulfur trioxide (143 g, 901 mmol, 3.00 equiv.) was added at 0–10 °C. The mixture was stirred at 0–10 °C for 2 h. TLC (petroleum ether:ethyl acetate=1:1, Rf(starting material)=0.30, Rf(product)=0.60) showed that the starting material was completely consumed. The mixture was poured into ice water (2.00 L) and extracted with EtOAc (500 mL×3), and the combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with petroleum ether:MTBE=10:1 (150 mL) to give 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, crude) as a dark brown solid. Step 3: Preparation of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine.

[0104] To a solution of 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, 258 mmol, 1.00 equiv.) and CH(OMe)3 (82.9 g, 780 mmol, 85.5 mL, 3.00 equiv.) in MeOH (210 mL), TsOH (897 mg, 5.21 mmol, 0.020 equiv.) was added. The mixture was then stirred at 65° C. for 16 h. TLC (petroleum ether:ethyl acetate=5:1, Rf(starting material)=0.30, Rf(product)=0.50) showed that the starting material was completely consumed. The resulting mixture was poured into saturated NaHCO3 (100 mL), extracted with EtOAc (100 mL×3), and the combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, 0-100 ethyl acetate / petroleum ether gradient, 60 mL / min) to give the desired 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (70.0 g, crude) as a white solid. 1H NMR (400 MHz CDCl3) δ 7.32 (d, J = 8.9 Hz, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 4.08 (d, J = 7.2 Hz, 1 H), 3.66 (br d, J = 12.4 Hz, 2 H), 3.38 (s, 6 H), 2.66 (td, J = 12.4, 2.0 Hz, 2 H), 1.67 - 1.91 (m, 3 H), 1.45 (qd, J = 12.4, 4.1 Hz, 2 H). Step 4: Preparation of 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one.

[0105] To a solution of resorcinol (230 g, 2.09 mol, 348 mL, 1.00 equiv.) and 3-chloropropanoic acid (249 g, 2.30 mol, 1.10 equiv.) at 40° C., CF3SO3H (1.10 kg, 7.31 mol, 645 mL, 3.50 equiv.) was added, and the mixture was then stirred at 80° C. for 1 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.21, Rf(product)=0.35) showed that the starting material was completely consumed. The resulting 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, crude) was used directly in the next step. Step 5: Preparation of 7-hydroxychroman-4-one.

[0106] Crude 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, 2.09 mol, 1.00 equiv.) was mixed with NaOH (584 g, 14.6 mol, 7.00 equiv.) in HO (1.59 L), and the mixture was then stirred at 0° C. for 30 min. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.40, Rf(product)=0.60) showed that the starting material was completely consumed. The reaction mixture was first adjusted to about pH 5 with 6N HCl, then extracted with EtOAc (2×1.50 L). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the desired crude product (342 g, crude) as a brown gum. Step 6: Preparation of 7-(benzyloxy)chroman-4-one.

[0107] To a solution of 7-hydroxychroman-4-one (342 g, 2.08 mol, 1.00 equiv.) in DMF (1.50 L) was added K2CO3 (575 g, 4.17 mol, 2.00 equiv.) and benzyl bromide (391 g, 2.29 mol, 272 mL, 1.10 equiv.), then the mixture was stirred at 15° C. for 12 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.20, Rf(product)=0.50) showed that the starting material was completely consumed. The mixture was poured into H2O (7.50 L) and extracted with EtOAc (2.00 L×2). The combined organic layers were washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=15:1 to 8:1) to give 7-(benzyloxy)chroman-4-one (185 g) as a white solid. LCMS m / z 255 (M+H)+. Step 7: Preparation of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol.

[0108] To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (63.0 g, 200 mmol, 1 equiv.) in 2-methyl-tetrahydrofuran (440 mL), n-BuLi (2.5 M, 96.2 mL, 1.30 equiv.) was added and the mixture was stirred at −78° C. for 1 h, then 7-(benzyloxy)chroman-4-one (50.9 g, 200 mmol, 1.00 equiv.) was added and the mixture was stirred at −78° C. for 1 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.15) showed that the starting material was completely consumed. The mixture was poured into H2O (300 mL) and extracted with EtOAc (50.0 mL x 2), and the combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether:EtOAc (500 mL) at 15 °C for 30 min to give 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol (72.0 g, crude) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.46 (m, 5 H), 7.25 (d, 2 H), 6.87 - 6.93 (m, 3 H), 6.48 - 6.53 (m, 2 H), 5.04 (s, 2 H), 4.35 - 4.42 (m, 1 H), 4.20 (dt, J = 11.2 Hz, 1 H), 4.09 (d, J = 7.2 Hz, 1 H), 3.72 (br d, J = 12.0 Hz, 2 H), 3.38 (s, 6 H), 2.68 (br t, J = 11.2 Hz, 2 H), 2.25 (m, 1H), 2.15 (m, 1H), 2.10 (s, 1H, OH), 1.86 (br d, J = 13.2 Hz, 2 H), 1.75 (ddq, J = 11.2 Hz, 1 H), 1.46 (br dd, J = 12.0 Hz, 2 H). Step 8: Preparation of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0109] To a solution of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol (66.0 g, 134 mmol, 1.00 equiv.) in MeOH (198 mL) was added TsOH (512 mg, 2.70 mmol, 2.07e-2 equiv.) and the mixture was stirred at 78° C. for 30 min. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.30, Rf(product)=0.60) showed that the starting material was completely consumed. The mixture was stirred at 25° C. for 30 min, filtered, and the cake was dried in vacuum to give 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (60.0 g, crude) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.46 (m, 5 H), 7.23 (br d, J = 8.2 Hz, 2 H), 6.92 - 7.02 (m, 3 H), 6.56 (s, 1 H), 6.50 (dd, J = 8.3 Hz, 2.3 Hz, 1 H), 5.62 (t, J = 4.0 Hz, 1 H), 5.05 (s, 2 H), 4.81 (d, J = 3.8 Hz, 2 H), 4.11 (d, J = 7.1 Hz, 1 H), 3.77 (br d, J = 12.0 Hz, 2 H), 3.39 (s, 6 H), 2.72 (t, J = 12.4 Hz, 2 H), 1.88 (br d, J = 13.6 Hz, 2 H), 1.74 - 1.82 (m, 1 H), 1.41 - 1.53 (m, 2 H). Step 9: Preparation of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0110] To a solution of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (60.0 g, 139 mmol, 1.00 equiv.) and DIEA (36.1 g, 279 mmol, 48.7 mL, 2.00 equiv.) in DMF (300 mL), pyridinium tribromide (71.6 g, 223 mmol, 1.60 equiv.) was added at 0° C. and the mixture was stirred at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.60) showed that the starting material was completely consumed. The mixture was poured into H2O (700 mL) and extracted with EtOAc (300 mL×2), the organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 30:1 to 0:1) to give 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (40.0 g, crude) as a yellow oil. LCMS m / z 550.2 and 552.2[M+H]+;1H NMR (400 MHz, CDCl3) δ 7.30 - 7.45 (m, 5 H), 7.14 (br d, J = 8.4 Hz, 2 H), 6.98 (br d, J = 8.4 Hz, 2 H), 6.67 (d, J = 8.6 Hz, 1 H), 6.52 (d, J = 1.7 Hz, 1 H), 6.43 (dd, J = 8.7 and 1.7 Hz, 1 H), 5.03 (s, 2H), 4.97 (s, 2H), 4.12 (d, J = 7.2 Hz, 1 H), 3.80 (br d, J = 12.4 Hz, 2 H), 3.40 (s, 6 H), 2.74 (br t, J = 11.8 Hz, 2 H), 1.89 (br d, J = 13.2 Hz, 2 H), 1.74 - 1.84 (m, 1 H),1.43 - 1.56 (m, 2 H). Step 10: Preparation of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0111] To a solution of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (33.0 g, 59.9 mmol, 1.00 equiv.) in DMF (140 mL) and HO (14 mL), phenylboronic acid (10.9 g, 89.9 mmol, 1.50 equiv.), KCO (16.5 g, 119 mmol, 2.00 equiv.), and Pd(dppf)Cl (855 mg, 1.17 mmol, 0.02 equiv.) were added and the mixture was stirred at 70° C. for 12 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.60) showed that the starting material was completely consumed. The mixture was poured into H2O (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with MeOH (100 mL) at 25 °C for 30 min to give 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (30.0 g, crude) as a grey solid. Step 11: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol.

[0112] To a solution of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (30.0 g, 54.7 mmol, 1.00 equiv.) in THF (30.0 mL) and EtOH (300 mL) was added Pd / C (3.00 g, 10.0% purity) and Pd(OH)2 / C (3.00 g, 20.0% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 60° C. under H2 (50 psi) for 12 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.20) showed that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was triturated with petroleum ether:EtOAc=10:1 (50.0 mL) at 25° C. for 30 min to give cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid. LCMS m / z 460.2[M+H]+;1H NMR (400 MHz, CDCl3) δ 7.11 - 7.20 (m, 3 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.62 - 6.73 (m, 4 H), 6.43 - 6.51 (m, 3 H), 6.35 (dd, J = 8.2, 2.5 Hz, 1 H), 4.77 (br s, 1 H, OH), 4.43 (t, J = 11.2 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 4.08 (d, J = 7.4 Hz, 1 H), 3.53 - 3.65 (m, 3 H), 3.37 (s, 6 H), 2.57 (t, J = 10.8 Hz, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.66 - 1.77 (m, 1 H), 1.38 - 1.49 (m, 2 H). Steps 12-15: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0113] This compound was prepared as the hydrochloride salt in four steps as described in the scheme: LC / MS 343.1[M+H]+; 1H-NMR (400 MHz, CD3OD) δ ppm 7.76 (d, J = 8.36 Hz, 1 H), 7.47 (s, 1 H), 7.35 (dd, J = 8.36, 1.54 Hz, 1 H), 5.09 (br dd, J = 12.8, 5.40 Hz, 1 H), 3.67 - 3.74 (m, 4 H), 3.37 - 3.42 (m, 4 H), 2.63 - 2.94 (m, 3 H), 2.07 - 2.17 (m, 1 H). Steps 16-17: Preparation of cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (compound 36).

[0114] To a solution of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol (50 mg, 0.11 mmol) in 2 mL of THF was added 2M aqueous sulfuric acid (2 mL, 4 mmol). The mixture was stirred at 70° C. for 30 min until all starting material was consumed. The mixture was adjusted to pH=9 with 1N NaOH solution and then extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give the crude aldehyde (50 mg). LC / MS m / z 413.9[M+H]+. The above crude aldehyde (50 mg, 0.09 mmol) was mixed with 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (37.8 mg, 0.1 mmol), TEA (18.2 mg, 0.18 mmol) in DCM (10 mL) followed by the addition of MgSO4 (108 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for 1 h. NaBH(AcO)3 (47.7 mg, 0.225 mmol) was then added in portions over 3 h. The reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative TLC using MeOH:DCM=1:10 to give the title compound (19.8 mg, 27.6%). LC / MS m / z 740.3[M+H]+;1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H, NH), 9.30 (s, 1H, OH), 7.69 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.19 - 7.14 (m, 3H), 6.78 (d, J = 3.2 Hz, 2H), 6.69 - 6.60 (m, 3H), 6.39 (d, J = 8.2 Hz, 2H), 6.33 - 6.27 (m, 2H), 5.08 (dd, 1H), 4.33 (t, J = 11 Hz, 1H), 4.22 - 4.17 (m, 2H), 3.60 - 3.51 (m, 3H), 3.44 (br s, 4H), 2.91 - 2.85 (m, 1H), 2.64 - 2.48 (m, 8H), 2.20 (br d, J = 7.4 Hz, 2H), 2.06-1.97 (m, 1H), 1.82 - 1.75 (m, 2H), 1.74 - 1.61 (m, 1H), 1.16 - 1.24 (m, 2H); Exact mass calculated for C44H45N5O6 by HRMS 739.3370, found [M+1] + 740.3421. Example 2: Synthesis of cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (compound 87). [ka] Step 1: Preparation of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol.

[0115] To a solution of compound 1,2-difluoro-4-nitrobenzene (100 g, 628 mmol, 69.4 mL, 1.00 eq.) and K2CO3 (130 g, 942 mmol, 1.50 eq.) in DMF (500 mL), piperidin-4-ylmethanol (76.0 g, 660 mmol, 1.05 eq.) was added at 0° C., and then the mixture was stirred at 25° C. for 12 hours. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.30) showed that the starting material was completely consumed. The mixture was poured into H2O (2.50 L), stirred for 20 min, filtered, and the cake was concentrated in vacuo to give (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 621 mmol, 98.8% yield) as a yellow solid. Step 2: Preparation of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol.

[0116] To a solution of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 424 mmol, 1.00 equiv) in MeOH (1.00 L) was added Pd / C (1.60 g, 10% purity) under argon. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 50° C. under H2 (50 psi) for 12 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.30, Rf(product)=0.10) showed that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo to give (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol as a brown solid. Step 3: Preparation of (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol.

[0117] To a solution of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (90.0 g, 401 mmol, 1.00 equiv.) in MeCN (360 mL) cooled to 0° C., HCl (12 M, 100 mL, 3.00 equiv.) was added, followed by dropwise addition of NaNO2 (33.2 g, 481 mmol, 1.20 equiv.) in H2O (40.0 mL) at 0° C., and the mixture was stirred for 0.5 h, followed by addition of KI (166 g, 1.00 mol, 2.50 equiv.) in H2O (100 mL) at 0° C. The mixture was stirred at 15° C. for 11 h. TLC (petroleum ether:ethyl acetate=1:1, Rf(starting material)=0.25, Rf(product)=0.10) showed that the starting material was completely consumed. The mixture was filtered and the cake was triturated with saturated NaOH (4M, 500 mL) at 15° C. for 30 min, filtered and the cake (brown solid) was used in the next step. Step 4: Preparation of 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde.

[0118] To a solution of NaHCO3 (46.8 g, 558 mmol, 1.70 equiv) and Na2CO3 (6.05 g, 57.1 mmol, 0.174 equiv) in HO (750 mL) was added (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol (110 g, 328 mmol, 1 equiv) in DCM (750 mL), then TBAB (10.6 g, 33.1 mmol, 0.101 equiv), TEMPO (1.29, 8.21 mmol, 0.020 equiv), and NCS (54.7 g, 410 mmol, 1.00 equiv) were added at 0 °C and the mixture was stirred at 0 °C for 1.5 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting matieral)=0.25, Rf(product)=0.50) showed that the starting material was completely consumed. The mixture was extracted with DCM (500 mL×2). The combined organic layers were washed with saturated Na2SO3 solution (200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde (90.0 g, crude) as a brown solid. Step 5: Preparation of 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine.

[0119] To a solution of 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde (90.0 g, 270 mmol, 1.00 equiv.) in MeOH (600 mL), CH(OCH3)3 (43.0 g, 405 mmol, 1.50 equiv.) and TsOH (6.98 g, 40.5 mmol, 0.150 equiv.) were added, and the mixture was then stirred at 65° C. for 12 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.35, Rf(product)=0.60) showed that the starting material was completely consumed. The pH was adjusted to 9 by slowly adding saturated NaHCO3. The mixture was concentrated under vacuum, then the mixture was added to H2O (200 mL) and extracted with EtOAc (500 mL x 2), and the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (90.0 g, 237 mmol, 87.7% yield) as a yellow solid. Step 6: Preparation of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol.

[0120] To a solution of 1-(4-iodo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (45 g, 118 mmol, 1.00 equiv.) in 2-methyl-tetrahydrofuran (225 mL), n-BuLi (2.5 M, 61.5 mL, 1.30 equiv.) was added at −65° C., the mixture was stirred at −65° C. for 0.5 h, and then 7-(benzyloxy)chroman-4-one (22.5 g, 88.9 mmol, 0.750 equiv.) in 2-methyl-tetrahydrofuran (100 mL) was added at −65° C., the mixture was stirred at −65° C. for 2.5 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.15) showed that the starting material was completely consumed. The same reaction was repeated again, and the two reactions were combined for workup. The mixture was poured into HO (300 mL) and extracted with EtOAc (50.0 mL×2), and the combined organic layers were washed with brine (50.0 ml), dried over NaSO, filtered, and concentrated in vacuo to give 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (85.0 g, crude) as a red solid. Step 7: Preparation of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0121] To a solution of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (85.0 g, 165 mmol, 1.00 equiv.) in MeOH (255 mL) was added TsOH (588 mg, 3.42 mmol, 0.021 equiv.) at 15° C. The mixture was stirred at 75° C. for 0.5 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.30, Rf(product)=0.60) showed that the starting material was completely consumed. The mixture was stirred at 25° C. for 30 min, filtered, and the cake was dried in vacuum to give 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (75.0 g, 140 mmol, 77.1% yield) as a red solid. 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.46 (m, 5 H), 6.88 - 7.06 (m, 4 H), 6.56 (d, J = 2.3 Hz, 1 H), 6.51 (dd, J = 8.6, 2.4 Hz, 1 H), 5.64 (t, J = 3.9 Hz, 1 H), 5.06 (s, 2 H), 4.80 (d, J = 3.9 Hz, 2 H), 4.12 (d, J = 7.2 Hz, 1 H), 3.53 (br d, J = 11.6 Hz, 2 H), 3.40 (s, 6 H), 2.68 (br t, J = 11.2 Hz, 2 H), 1.87 (br d, J = 12.8 Hz, 2H), 1.76 (m, 1H), 1.45-1.65 (m, 2H). Step 8: Preparation of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0122] To a solution of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (75.0 g, 153 mmol, 1.00 equiv.) and DIEA (59.0 g, 459 mmol, 80.0 mL, 3.00 equiv.) in DMF (350 mL) was added pyridinium tribromide (73.0 g, 245 mmol, 1.60 equiv.) at °C under N2. The mixture was stirred at 15 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) showed that the starting material was completely consumed. The mixture was poured into H2O (1.00 L) and extracted twice with EtOAc (300 mL), and the organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with MTBE (250 mL) at room temperature for 30 min to give 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (90.0 g, crude) as a red solid. 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.49 (m, 5 H), 6.85 - 7.06 (m, 3 H), 6.63 (m, 1 H), 6.53 (d, J = 2.20 Hz, 1 H), 6.44 (dd, J = 8.6, 2.4 Hz, 1 H), 5.03 (s, 2H), 4.98 (s, 2 H), 4.13 (d, J = 7.3 Hz, 1 H), 3.50 - 3.62 (m, 2 H), 3.40 (s, 6 H), 2.71 (br t, J = 11.2 Hz, 2 H), 1.70 - 1.93 (m, 3 H), 1.56 (qd, J = 12.0, 3.6 Hz, 2 H). Step 9: Preparation of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0123] To a solution of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (85.0 g, 148 mmol, 1.00 equiv.) in DMF (400 mL) and H2O (40.0 mL) was added phenylboronic acid (25.4 g, 208 mmol, 1.40 equiv.), K2CO3 (45.7 g, 330 mmol, 2.22 equiv.), and Pd(dppf)Cl2 (2.50 g, 3.429 mmol, 0.023 equiv.). The mixture was stirred at 70 °C under N2 for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.55) showed that the starting material was completely consumed. The mixture was poured into H2O (1.50 L) and stirred for 30 min at 15° C. The solid was filtered and the cake was dried in vacuum to give 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (60.0 g, crude) as a red solid. 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.49 (m, 5 H), 7.07 - 7.22 (m, 3 H), 6.98 (d, 2 H), 6.72 - 6.88 (m, 4 H), 6.65 (s, 1 H), 6.50 (d, 1 H), 5.06 (br s, 4 H), 4.11 (br dd, J = 5.6, 1.2 Hz, 1 H), 3.46 - 3.53 (m, 2 H), 3.39 (s, 6 H), 2.63 (t, J = 11 Hz, 2 H), 1.87 (br d, 2 H), 1.75 (m, 1H), 1.45 - 1.63 (m, 2H). Step 10: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol.

[0124] To a solution of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (30.0 g, 53.1 mmol, 1.00 equiv.) in THF (75.0 mL) and EtOH (300.0 mL) was added Pd / C (3 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 50° C. under H2 (50 psi) for 12 h. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.20) showed that the starting material was completely consumed. The resulting mixture was filtered and the filtarte was concentrated in vacuo. The hydrogenation reaction was repeated on the same scale and the two reactions were combined for purification. The crude product was triturated with petroleum ether: EtOAc = 10: 1 (200 mL) at 25 ° C for 30 min to give cis-4- (4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorophenyl) -3-phenylchroman-7-ol (50.0 g, purity 96.8%) as an off-white solid. LCMS m / z 478.2[M+H]+;1H NMR (400 MHz, CDCl3) δ 7.12 - 7.23 (m, 3 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.60 - 6.73 (m, 3 H), 6.46 (d, J = 2.4 Hz, 1 H), 6.38 (dd, J = 8.3, 2.6 Hz, 1 H), 6.22 - 6.30 (m, 2 H), 4.72 (br s, 1 H), 4.41 (t, J = 11.2 Hz, 1 H), 4.25 (dd, J = 10.8, 2.4 Hz, 1 H), 4.19 (d, J = 5.2 Hz, 1 H), 4.09 (d, J = 7.4 Hz, 1 H), 3.54 - 3.61 (m, 1 H), 3.37 (s and m, 8 H), 2.54 (br t, J = 11.8 Hz, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.65 - 1.76 (m, 1 H),1.43 - 1.56 (m, 2 H). Step 11: Preparation of cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (Compound 87).

[0125] This reaction step was carried out using the same method as described in steps 16-17 of Example 1. LC / MS m / z 758.7[M+H]+;1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.36 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.22 - 7.08 (m, 3H), 6.86 - 6.64 (m, 4H), 6.38 - 6.26 (m, 3H), 6.15 (d, J = 14.0 Hz, 1H), 5.08 (dd, J = 13.0, 5.4 Hz, 1H), 4.33 (t, J = 11 Hz, 1H), 4.26 - 4.21 (m, 2H), 3.60 - 3.52 (m, 1H), 3.49 - 3.39 (br s, 4H), 3.27 - 3.18 (m, 2H), 2.93 - 2.84 (m, 1H), 2.69 - 2.48 (m, 8H), 2.20 (br d, 2H), 2.07 - 1.96 (m, 1H), 1.83 - 1.73 (m, 2H), 1.70 - 1.60 (m, 1H), 1.16 - 1.24 (m, 2H); Exact mass calculated for C44H44FN5O6 by HRMS 757.3276, observed [M+1] + 758.3336. Example 3: Synthesis of (S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 41). [ka] Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate.

[0126] To a mixture of 2-bromo-4,5-difluorobenzoic acid (200 g, 0.84 mol) in MeOH (600 mL) was slowly added thionyl chloride (130 g, 1.09 mol) at 10° C., and the mixture was stirred at 80° C. for 3 h. TLC showed the reaction was complete. The mixture was cooled to room temperature, concentrated, and then partitioned between ethyl acetate and water. The organic layer was washed twice with saturated Na2CO3 and brine, dried over Na2SO4, and concentrated to give crude methyl 2-bromo-4,5-difluorobenzoate (210 g, yield: 100%), which was used in the next step without further purification. Step 2: Preparation of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0127] A mixture of methyl 2-bromo-4,5-difluorobenzoate (210 g, 0.84 mol), tert-butyl piperazine-1-carboxylate (234 g, 1.25 mol) and K2CO3 (173 g, 1.25 mol) in N,N-dimethylacetamide (600 mL) was stirred at 80 °C for 16 h. TLC showed the reaction was complete. The mixture was added to water (2 L) and stirred for 10 min, after which ethyl acetate was added. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (315.8 g, yield: 90%). Step 3: Preparation of tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0128] A mixture of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (306 g, 0.73 mol) and CuCN (98 g, 1.09 mol) in DMF (1.2 L) was stirred at 100° C. for 16 h. TLC showed the reaction was complete. The mixture was cooled to room temperature. Ethyl acetate (2 L) and ammonium hydroxide (2 L) were added and the mixture was stirred for 30 min. The mixture was filtered. The organic layer was washed with water, dried over Na2SO4, and concentrated to give the crude product (254 g). The crude product was taken up in petroleum ether (1 L) at reflux. The mixture was filtered and dried in an oven at 50° C. to give tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (215 g, yield: 81%). Step 4: Preparation of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0129] To a solution of pyridine (391 g, 4.95 mol), water (200 mL), acetic acid (264 g, 4.4 mol) was added tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (200 g, 0.55 mol) and Raney Nickel (85% in water, 100 g) at room temperature. The resulting mixture was heated to 60° C. Sodium hypophosphite (292 g in 500 mL water) was added dropwise into the mixture. The mixture was stirred at 60° C. for 16 hours. TLC showed that the reaction was not complete. The mixture was stirred for an additional 10 hours. The mixture was cooled to room temperature. Ethyl acetate and water were added. The mixture was filtered. The organic layer was washed with water, 1N HCl and brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product (208 g, crude), which was further purified by silica gel pad to give 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (86.5 g, yield: 43%). Step 5: Preparation of tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate.

[0130] To a solution of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (81.5 g, 0.22 mol) in methanol (500 mL) was added tert-butyl (S)-4,5-diamino-5-oxopentanoate (54 g, 0.27 mol) at room temperature. Acetic acid (19.8 g, 0.33 mol) was added at 0° C., followed by slow addition of sodium cyanoborohydride (27.6 g, 0.44 mol). The mixture was stirred at room temperature for 16 hours. TLC showed the reaction was complete. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated citric acid, brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by silica gel pad to give tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (80 g, yield: 69%). Step 6: Preparation of (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonic acid.

[0131] To a solution of (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (67 g, 0.13 mol) in acetonitrile (670 mL) was added benzenesulfonic acid (43 g, 0.26 mol). The mixture was stirred at 80° C. for 16 h. LCMS showed the reaction was complete. The mixture was cooled to room temperature. The mixture was filtered and dried to give (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (56 g, 86%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.94-1.99 (m, 1H), 2.35-2.43 (m, 1H), 2.58-2.62 (m, 1H), 2.88-2.91 (m, 1H), 3.30 (br s, 8H), 4.38 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 7.29-7.35 (m, 4H), 7.49 (d, J = 8.7 Hz, 1H), 7.60 (m, 2H), 8.72 (s, 2H), 10.99 (s, 1H). LCMS m / z 347.3[M+1] + . Step 7: Preparation of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol.

[0132] Racemic cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (50.0 g, 104 mmol) prepared in step 10 of compound 87 was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 60%-60%).

[0133] The first fraction collected gave (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (15.0 g, 99.4% purity) as an off-white solid. [α] D 25 =335.8(1g / 100mL in EtOAc);LCMS m / z 478.2[M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.12 - 7.23 (m, 3 H), 6.65 - 6.86 (m, 4 H), 6.25-6.35 (m, 3H), 6.13 (d, 1H), 4.30 (t, 1H), 4.23 (m, 2H), 4.07 (d, J = 6.4 Hz, 1H), 3.53 (m, 1H), 3.25 (s, 6H), 3.15-3.24 (m, 2H), 2.42-2.50 (m, 2H), 1.57-1.72 (m, 3H), 1.22-1.40 (m, 2H).

[0134] The second fraction collected gave (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (16.0 g, 98.1% purity) as a brown solid. [α] D 25 =-303.9(0.5g / 100mL in EtOAc);LCMS m / z 478.2[M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 1H), 7.16 (m, 3 H), 6.65 - 6.80 (m, 4 H), 6.25-6.32 (m, 3H), 6.13 (d, J = 13.6 Hz, 1H), 4.32 (t, 1H), 4.17-4.27 (m, 2H), 4.07 (d, J = 6.4 Hz, 1H), 3.55 (m, 1H), 3.25 (s, 6H), 3.16-3.25 (m, 2H), 2.40-2.50 (m, 2H), 1.57-1.72 (m, 3H), 1.22-1.37 (m, 2H). Step 8: Preparation of (S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 41).

[0135] The separated (-)-enantiomer from step 7 was first deprotected under acidic conditions and then reacted with the product from step 6 under conditions identical to those described in step 11 for the preparation of compound 87. LCMS m / z 762.2 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.35 (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 7.27 - 7.16 (m, 4H), 6.82 - 6.72 (m, 3H), 6.68 (d, J = 8.2 Hz, 1H), 6.35 - 6.28 (m, 3H), 6.15 (d, J = 14.1 Hz, 1H), 5.08 (dd, 1H), 4.43 - 4.18 (m, 5H), 3.63 - 3.53 (m, 1H), 3.32 - 3.30 (m, 2H), 3.26 - 3.20 (m, 2H), 3.12 (br s, 2H), 2.95-2.85 (m, 1H), 2.63 - 2.48 (m, 7H), 2.42 - 2.32 (m, 1H), 2.22 (br d, 2H), 2.02 - 1.91 (m, 1H), 1.81 - 1.73 (m, 2H), 1.70-1.61 (m, 1H), 1.27 - 1.20 (m, 2H); Exact mass calculated for C44H45F2N5O5 by HRMS 761.3389, observed [M+1] + 762.3593. Example 4: Synthesis of (S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 42). [ka] Step 1: Preparation of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol.

[0136] Racemic cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol (49.2 g, 108 mmol) prepared in step 11 of compound 36 was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm×50 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 50%-50%, 5.5 min). The first fraction collected gave (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid (19.0 g, 97.8% purity). [α] D 25 =360.4(1.34g / 100mL in EtOAc);LCMS m / z 460.2[M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.11 - 7.20 (m, 3 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.62 - 6.73 (m, 4 H), 6.43 - 6.51 (m, 3 H), 6.35 (dd, J = 8.2, 2.5 Hz, 1 H), 4.84 (br s, 1 H, OH), 4.43 (t, J = 11.2 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 4.08 (d, J = 7.4 Hz, 1 H), 3.53 - 3.65 (m, 3 H), 3.37 (s, 6 H), 2.58 (dt, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.66 - 1.77 (m, 1 H), 1.38 - 1.49 (m, 2 H). The second fraction collected gave (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid (19.0 g, 99.8% purity). [α] D 25 =-386.8(0.39g / 100mL in EtOAc);LCMS m / z 460.2[M+1] + ; 1H NMR (400 MHz, CDCl3) δ 7.11 - 7.20 (m, 3 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.62 - 6.73 (m, 4 H), 6.43 - 6.51 (m, 3 H), 6.35 (dd, J = 8.2, 2.5 Hz, 1 H), 4.79 (br s, 1 H, OH), 4.43 (t, J = 11.2 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 4.07 (d, J = 7.4 Hz, 1 H), 3.53 - 3.65 (m, 3 H), 3.37 (s, 6 H), 2.58 (dt, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.66 - 1.77 (m, 1 H), 1.35 - 1.49 (m, 2 H). Step 2: Preparation of (S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 42).

[0137] This compound was prepared using the separated (-)-enantiomer from step 1 under conditions identical to those described for the synthesis of compound 41. LCMS m / z 744.2 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.29 (s, 1H), 7.43 (d, J = 11.3 Hz, 1H), 7.27 - 7.12 (m, 4H), 6.80 - 6.74 (m, 2H), 6.69 - 6.59 (m, 3H), 6.38 (d, J = 8.1 Hz, 2H), 6.33 - 6.24 (m, 2H), 5.08 (dd, 1H), 4.42 - 4.15 (m, 5H), 3.67 - 3.50 (m, 3H), 3.23 (m, 2H), 3.12 (br s, 2H), 2.95-2.85 (m, 1H), 2.67 - 2.50 (m, 7H), 2.41 - 2.30 (m, 1H), 2.20 (br d, 2H), 2.02 - 1.90 (m, 1H), 1.82 - 1.74 (m, 2H), 1.69 - 1.60 (m, 1H), 1.26 - 1.10 (m, 2H); Exact mass calculated for C44H46FN5O5 by HRMS 743.3483, observed [M+1] + 744.3681. Example 5: Synthesis of (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 86). [ka]

[0138] This compound was prepared using the same method as for the preparation of compound 41. The desired compound was obtained as a neutral white solid after purification. LCMS m / z 743.7 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.37 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.17 (m, 3H), 7.07 (s, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.84 - 6.71 (m, 3H), 6.69 (d, J = 8.3 Hz, 1H), 6.37-6.27 (m, 3H), 6.16 (br d, J = 12 Hz, 1H), 5.06 (dd, J = 12.5 Hz, 4.2 Hz, 1H), 4.40 - 4.18 (m, 5H), 3.57 (m, 1H), 3.32 - 3.17 (m, 6H), 2.96 - 2.87 (m, 1H), 2.60 - 2.48 (m, 7H), 2.40 - 2.33 (m, 1H), 2.22 (br d, 2H), 2.00-1.90 (br d, 1H), 1.80-1.75 (m, 2H), 1.70-1.60 (m, 1H), 1.28 - 1.20 (m, 2H); Exact mass calculated for C44H46FN5O5 by HRMS 743.3483, observed [M+1] + 744.3567. Example 6: Synthesis of (S)-3-(5-(4-((1-(2-fluoro-4-((3R,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 45). [ka]

[0139] This compound was prepared using the same method as for preparing compound 41. LCMS m / z 743.5 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.37 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.20 - 7.06 (m, 5H), 6.82 - 6.78 (m, 2H), 6.78 - 6.72 (m, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.34 - 6.29 (m, 3H), 6.16 (d, J = 14.3 Hz, 1H), 5.06 (dd, J = 13.2, 4.8 Hz, 1H), 4.43 - 4.09 (m, 5H), 3.59 - 3.54 (m, 1H), 3.34 - 3.19 (m, 6H), 2.94 - 2.86 (m, 1H), 2.69 - 2.48 (m, 7H), 2.46 - 2.31 (m, 1H), 2.20 (br, 2H), 1.98 - 1.92 (m, 1H), 1.85 - 1.60 (m, 3H), 1.29-1.20 (m, 2H); Exact mass calculated for C44H46FN5O5 by HRMS 743.3483, found [M+1] + 744.3567. Example 7: Synthesis of (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 33). [ka]

[0140] This compound was prepared using the same method as for preparing compound 41. LCMS m / z 725.7 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.31 (s, 1H), 7.53 - 7.51 (m, 1H), 7.25 - 7.02 (m, 5H), 6.77 (m, 2H), 6.73-6.60 (m, 3H), 6.40 (d, J = 8.3 Hz, 2H), 6.33 - 6.25 (m, 2H), 5.06 (dd, 1H), 4.39 - 4.31 (m, 2H), 4.26 - 4.17 (m, 3H), 3.64 - 3.50 (m, 3H), 3.28 - 3.25 (br s, 4H), 2.94 - 2.89 (m, 1H), 2.64 - 2.48 (m, 7H), 2.41 - 2.33 (m, 1H), 2.19 (br, 2H), 2.00 - 1.93 (m, 1H), 1.86 - 1.60 (m, 3H), 1.29 - 1.12 (m, 2H); Exact mass calculated for C44H47N5O5 by HRMS 725.3577, observed [M+1] + 726.3675. Example 8: Synthesis of (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 34). [ka] This compound was prepared using the same method as for preparing compound 41. LCMS m / z 725.5 [M+H] +;H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.32 (s, 1H), 7.62 - 7.58 (m, 1H), 7.34 - 7.30 (m, 1H), 7.19 - 7.06 (m, 4H), 6.83 - 6.74 (m, 2H), 6.72 - 6.54 (m, 3H), 6.40 (d, J = 7.5 Hz, 2H), 6.35 - 6.20 (m, 2H), 5.07 (br d, J = 8.8 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.27 - 4.14 (m, 3H), 3.64 - 3.51 (m, 3H), 3.31 - 3.27 (m, 4H), 2.94 - 2.87 (m, 1H), 2.70 - 2.54 (m, 7H), 2.40 - 2.31 (m, 1H), 2.24 - 2.15 (m, 2H), 2.03 - 1.65 (m, 4H), 1.30 - 1.20 (m, 2H); Exact mass calculated for C44H47N5O5 by HRMS 725.3577, observed [M+1] + 726.3702. Example 9: Synthesis of cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 32). [ka] This compound was prepared using the same method as for preparing compound 41. LCMS m / z 725.5 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.31 (s, 1H), 7.62 - 7.51 (m, 1H), 7.23 - 7.04 (m, 5H), 6.81 - 6.74 (m, 2H), 6.71 - 6.58 (m, 3H), 6.39 (d, J = 8.1 Hz, 2H), 6.32 (d, J = 2.2 Hz, 1H), 6.31 - 6.26 (m, 1H), 5.06 (dd, J = 13.1, 4.4 Hz, 1H), 4.34 (t, J = 11.1 Hz, 2H), 4.28 - 4.15 (m, 3H), 3.66 - 3.47 (m, 3H), 3.33 - 3.26 (m, 4H), 2.96 - 2.86 (m, 1H), 2.70 - 2.48 (m, 7H), 2.46 - 2.31 (m, 1H), 2.20 (br s, 2H), 2.02 - 1.60 (m, 4H), 1.30 - 1.15 (m, 2H); Exact mass calculated for C44H47N5O5 by HRMS 725.3577, observed [M+1] + 726.3641. Example 10: cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 85). [ka] This compound was prepared using the same method as for preparing compound 41. LCMS m / z 744.3 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.37 (s, 1H), 7.57-7.49 (m, 1H), 7.21 - 7.04 (m, 5H), 6.83 - 6.67 (m, 4H), 6.37 - 6.27 (m, 3H), 6.16 (d, J = 14.6 Hz, 1H), 5.06 (dd, J = 13.3, 5.0 Hz, 1H), 4.41 - 4.16 (m, 5H), 3.59 - 3.54 (m, 1H), 3.34 - 3.16 (m, 6H), 2.95 - 2.86 (m, 1H), 2.69 - 2.48 (m, 7H), 2.44 - 2.33 (m, 1H), 2.20 (br s, 2H), 1.99 - 1.90 (m, 1H), 1.82-1.74 (m, 2H), 1.72-1.60 (m, 1H), 1.25-1.15 (m, 2H); Exact mass calculated for C44H46FN5O5 by HRMS 743.3483, found [M+H] + 744.3530. Example 11: Synthesis of cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 60). [ka] Step 1: Preparation of 1-(4-(7-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine To a solution of 1-{4-[7-(benzyloxy)-3-bromo-2H-chromen-4-yl]-2-fluorophenyl}-4-(dimethoxymethyl)piperidine (200 mg, 0.35 mmol), (4-fluoro-3-methylphenyl)boranediol (80.82 mg, 0.52 mmol) and potassium carbonate (145.12 mg, 1.05 mmol) in DMF and HO (10 mL / 10 mL) stirred at room temperature under nitrogen atmosphere was added 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (25.60 mg, 0.034 mmol). The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 12 hours. The resulting mixture was evaporated in vacuum to give the crude product, which was dissolved in DCM (200 mL), washed with water (20 mL) and evaporated in vacuum. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate=2:1) ​​to give the desired product as a brown solid (150 mg, 0.29 mmol, 71.3% yield). Step 2: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(4-fluoro-3-methylphenyl)chroman-7-ol. To a solution of 1-(4-(7-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (130 mg, 0.26 mmol) in THF (20 mL) stirred at room temperature was added palladium on carbon (553.38 mg, 5.2 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product as a yellow solid (130 mg, 0.25 mmol, 85.3% yield). LCMS m / z 509.7[M+1] + . Step 3: Preparation of cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 60). A solution of 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(4-fluoro-3-methylphenyl)chroman-7-ol (100 mg, 0.2 mmol)) in THF (5 mL) and water (5 ml, containing 10% H2SO4) was stirred at 70° C. for 1 h. The reaction mixture was dissolved in DCM (200 mL), adjusted to pH 10 with aqueous sodium hydroxide (2 M) and the organic layer was evaporated in vacuo to give the desired product as a yellow solid (80 mg, 0.17 mmol, 86.3% yield). LCMS m / z 463.7 [M+1] + To this solid (30 mg, 0.06 mmol) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (29.19 mg, 0.06 mmol) and triethylamine (30.35 mg, 0.3 mmol) in DCM (5 mL). The mixture was stirred at room temperature after addition of MgSO4 (72.00 mg, 0.60 mmol). After further stirring the reaction mixture at room temperature for 2 h, sodium triacetoxyborohydride was added in portions (38.15 mg, 0.18 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h and then filtered. The filtrate was evaporated in vacuo to give the crude product, which was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product as a white solid (20 mg, 0.03 mmol, 50.0% yield). LCMS m / z 775.5[M+1] + ; 1H NMR (400 MHz, DMSO) δ = 10.95 (s, 1H), 9.36 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.93 (t, J=9.0 Hz, 1H), 6.77 (t, J=8.8 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.64 - 6.59 (m, 2H), 6.36 - 6.25 (m, 3H), 6.20 (d, J=14.1 Hz, 1H), 5.06 (dd, 1H), 4.36 - 4.12 (m, 5H), 3.59 - 3.47 (m, 1H), 3.30 - 3.19 (m, 6H), 2.90 - 2.86 (m, 1H), 2.68 - 2.48 (m, 7H), 2.38 - 2.29 (m, 1H), 2.23-2.20 (br d, 2H), 2.08 (s, 3H), 2.01 - 1.92 (m, 1H), 1.79 - 1.76 (m, 2H), 1.70 - 1.62 (m, 1H), 1.26 - 1.15 (m, 2H); Exact mass calculated for C45H47F2N5O5 by HRMS 775.3545, observed [M+1] + 776.3584 Example 12: Synthesis of cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 52). [ka]

[0141] This compound was prepared using the same procedure as described in Example 11. LC / MS: 757.5 [M+1] + ; 1H NMR (400 MHz, DMSO) δ = 10.95 (s, 1H), 9.35 (s, 1H), 7.52 (d, J =8.1 Hz, 1H), 7.16 - 7.02 (m, 3H), 6.98 (d, J =7.8 Hz, 1H), 6.75 (t, J =8.9 Hz, 1H), 6.68 (d, J =8.2 Hz, 1H), 6.58 (d, J =7.4 Hz, 1H), 6.51 (s, 1H), 6.30 - 6.24 (m, 3H), 6.16 (d, J =13.9 Hz, 1H), 5.06 (dd, 1H), 4.38 - 4.10 (m, 5H), 3.52 - 3.47 (m, 1H), 3.30 - 3.20 (m, 6H), 2.95 - 2.87 (m, 1H), 2.72 - 2.48 (m, 7H), 2.42 - 2.30 (m, 1H), 2.22 - 2.19 (br, 2H), 2.15 (s, 3H), 1.99 - 1.90 (m, 1H), 1.78 (m, 2H), 1.70 - 1.63 (m, 1H), 1.25 - 1.10 (m, 2H); Exact mass calculated for C45H48FN5O5 by HRMS 757.3639, observed [M+1] + 758.3681. Example 13: Synthesis of cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 84). [ka]

[0142] This compound was prepared using the same procedure as described in Example 11. LC / MS: m / z 779.4 [M+1] + ; 1H NMR (400 MHz, DMSO) δ = 10.95 (s, 1H), 9.38 (s, 1H), 7.53 - 7.51 (m, 1H), 7.28 - 7.21 (m, 1H), 7.08 - 7.04 (m, 2H), 6.88 - 6.74 (m, 2H), 6.69 - 6.66 (m, 2H), 6.34 - 6.23 (m, 4H), 5.06 (dd, 1H), 4.35 - 4.15 (m, 5H), 3.65 - 3.54 (m, 1H), 3.33 - 3.23 (m, 6H), 2.98 - 2.84 (m, 1H), 2.62 - 2.41 (m, 7H), 2.38 - 2.34 (m, 1H), 2.20 (br d, 2H), 2.03 - 1.93 (m, 1H), 1.80 - 1.69 (m, 2H), 1.68 - 1.60 (m, 1H), 1.26 - 1.16 (m, 2H); Exact mass calculated for C44H44F3N5O5 by HRMS 779.3295, observed [M+1] + 780.3345. Example 14: Synthesis of cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 56) [ka] Step 1: Preparation of 1-(4-(7-(benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine To a solution of 1-{4-[7-(benzyloxy)-3-bromo-2H-chromen-4-yl]phenyl}-4-(dimethoxymethyl)piperidine (100 mg, 0.18 mmol), 3-methoxyphenylboronic acid (41.02 mg, 0.27 mmol) and potassium carbonate (74.63 mg, 0.54 mmol) in DMF / HO (20 mL, DMF / HO=5:1) stirred at room temperature under nitrogen, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (26.34 mg, 0.036 mmol) was added. The reaction mixture was stirred at 60° C. under nitrogen for 5 h. The reaction mixture was filtered and evaporated in vacuum to give the crude product. The crude product was dissolved in DCM (200 mL), washed with water (20 mL) and the organic layer was dried over sodium sulfate, filtered and evaporated in vacuum. The resulting residue was purified by preparative TLC (PE:EA=5:1) to give the desired product (80 mg, 0.14 mmol, 76.1% yield) as a yellow solid. LC / MS: 578.1 [M+1] + . Step 2: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol To a solution of 1-{4-[7-(benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl]phenyl}-4-(dimethoxymethyl)piperidine (100 mg, 0.17 mmol) in THF (15 mL) stirred at room temperature under hydrogen was added palladium on carbon (180 mg). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and evaporated in vacuo to give the desired product (80 mg, 0.16 mmol, 96.1%) as a yellow solid. LC / MS: 489.9 [M+1] + . Step 3: Preparation of cis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde A solution of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol (100 mg, 0.2 mmol) in THF / H2SO4 (10% aqueous solution) (20 mL, THF / H2SO4=1 / 1) was stirred at 70° C. for 2 h. The reaction mixture was adjusted to about pH 12 with sodium hydroxide solution (2 mol / L), extracted with DCM (200 mL), dried over sodium sulfate, and evaporated in vacuum to give the desired product (80 mg, 0.18 mmol, 88% yield) as a yellow solid. LC / MS: 443.3 [M+1] + . Step 4: Preparation of cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 56) A solution of cis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (24.32 mg, 0.05 mmol), TEA (0.25 mmol), and MgSO4 (60 mg, 0.5 mmol) in DCM (5 mL) was stirred at room temperature under nitrogen for 30 min. Then, sodium triacetoxyborohydride (31.79 mg, 0.15 mmol) was added in portions at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, the organic layer was washed with water, and extracted with DCM (50 mL) to give the crude product. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (45 mg, 0.06 mmol, 53%) as a white solid. LC / MS: 756.2 [M+1] + ; 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.27 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.15 - 6.99 (m, 3H), 6.74 - 6.59 (m, 4H), 6.42 (d, J = 8.6 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 6.34 - 6.16 (m, 3H), 5.06 (dd, 1H), 4.41 - 4.15 (m, 5H), 3.61 - 3.52 (m, 5H), 3.50 - 3.44 (m, 1H), 3.28 (br s, 4H), 2.98 - 2.84 (m, 1H), 2.66 - 2.51 (m, 7H), 2.37 - 2.31 (m, 1H), 2.19 (br d, 2H), 2.02 - 1.90 (m, 1H), 1.80 - 1.73 (m, 2H), 1.69 - 1.60 (m, 1H), 1.25 - 1.16 m, 2H); exact mass calculated for C45H49N5O6 by HRMS 755.3683, found [M+H] + 756.3753. Example 15: Synthesis of cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 63) [ka] This compound was prepared using the same method as described in Example 14, except that 4-fluoro-3-methylphenylboronic acid was used. The crude product from the final reductive amination step was purified by preparative TLC to give the desired compound (65 mg, 0.084 mmol, 38.9% yield) as a white solid. LC / MS: 773.6 [M+1] + ; 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.29 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.12-7.03 (m, 2H), 6.98 (dd, J = 11.5, 8.3 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 3H), 6.44 (d, J = 8.5 Hz, 2H), 6.41 - 6.33 (m, 2H), 6.33 - 6.25 (m, 2H), 5.05 (dd, J = 13.2, 5.0 Hz, 1H), 4.37 - 4.25 (m, 2H), 4.24 - 4.18 (m, 1H), 4.18 - 4.10 (m, 2H), 3.61 - 3.48 (m, 6H), 3.28 (br s, 4H), 2.96 - 2.83 (m, 1H), 2.64 - 2.51 (m, 7H), 2.46 - 2.29 (m, 1H), 2.20 (br s, 2H), 2.01 - 1.93 (m, 1H), 1.83 - 1.74 (m, 2H), 1.73 - 1.63 (br, 1H), 1.27 - 1.12 (m, 2H); Exact mass calculated for C45H48FN5O6 by HRMS 773.3589, observed [M+1] + 774.3818. Example 16: Synthesis of cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 74) [ka] This compound was prepared using the same method as described in Example 14, except that (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate was used in the final reductive amination step. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (25 mg, 48% yield) as a white solid. LC / MS: 774.1 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.28 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.75 - 6.58 (m, 4H), 6.45 - 6.33 (m, 3H), 6.30 - 6.15 (m, 3H), 5.08 (dd, 1H), 4.38 - 4.09 (m, 5H), 3.58 (s, 3H), 3.57 - 3.52 (m, 2H), 3.52 - 3.43 (m, 1H), 3.21 - 3.04 (m, 4H), 2.99 - 2.85 (m, 1H), 2.69 - 2.53 (m, 7H), 2.49 - 2.28 (m, 1H), 2.20 (br d, 2H), 2.02 - 1.94 (m, 1H), 1.80 - 1.60 (m, 3H), 1.30 - 1.10 (m, 2H); Exact mass calculated for C45H48FN5O6 by HRMS 773.3589, observed [M+1] + 774.3688. Example 17: Synthesis of cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 89) [ka] This compound was prepared using the same method as described in Example 14, except that 4-methoxyphenylboronic acid was used. The crude product from the final step of reductive amination was purified by preparative TLC (DCM:MeOH=5:1) to give the desired compound as a white solid. LC / MS: 756.2 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ = 10.94 (s, 1H), 9.26 (s, 1H), 7.52 (d, J=8.5, 1H), 7.05 (m, 2H), 6.79 - 6.56 (m, 7H), 6.40 (d, J=8.6, 2H), 6.33 - 6.23 (m, 2H), 5.08 - 5.01 (m, 1H), 4.36 - 4.11 (m, 5H), 3.68 (s, 3H), 3.60 - 3.52 (m, 2H), 3.48 - 3.42 (m, 1H), 3.31 - 3.25 (m, 4H), 2.95 - 2.84 (m, 1H), 2.67 - 2.42 (m, 7H), 2.46 - 2.28 (m, 1H), 2.19 (br d, 2H), 2.00 - 1.92 (m, 1H), 1.77 (m, 2H), 1.69 - 1.63 (m, 1H), 1.27 - 1.10 (m, 2H); Exact mass calculated for C45H49N5O6 by HRMS 755.3683, found [M+1] + 756.3763. Example 18: Synthesis of cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 90) [ka] This compound was prepared using the same method as described in Example 17, except that (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate was used in the final reductive amination step. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give the desired compound as a white solid. LC / MS: 774.2 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.30 (s, 1H), 7.43 (d, J = 11.5 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 6.77 - 6.57 (m, 7H), 6.40 (d, J = 8.5 Hz, 2H), 6.34 - 6.20 (m, 2H), 5.05 (dd, 1H), 4.45 - 4.12 (m, 5H), 3.68 (s, 3H), 3.58 -3.48 (m, 3H), 3.26 - 3.05 (m, 4H), 2.95 - 2.87 (m, 1H), 2.69- 2.46 (m, 7H), 2.45 - 2.28 (m, 1H), 2.22 (br, 2H), 2.03 -1.95 (m, 1H), 1.79 - 1.65 (m, 3H), 1.30 - 1.16 (m, 2H); Exact mass calculated for C45H48FN5O6 by HRMS 773.3589, observed [M+1] + 774.3648. Example 19: ERα degradation activity of compounds of the present disclosure in T47D, MCF7, and CAMA1 cells.

[0143] T47D cells were cultured at 1.5 × 10 in 24-well plates in RPMI growth medium containing 10% FBS and 1 × penicillin-streptomycin. 5 MCF7 cells were plated at 1.5 × 10 cells / well in 24-well plates in DMEM growth medium containing 10% FBS and 1 × penicillin-streptomycin. 5CAMA1 cells were plated at 2 × 10 cells / well in 24-well plates in RPMI growth medium containing 20% ​​FBS and 1 × penicillin-streptomycin. 5 Cells were plated in wells at 37°C. They were then incubated overnight at 37°C. The next day, cells were dosed with test compounds by using 1000x compound stock solutions prepared in DMSO at various concentrations. After compound administration, cells were then incubated at 37°C for 6 hours.

[0144] Upon completion, cells were washed with PBS and proteins were collected in Laemmli sample buffer (1x; VWR International). Proteins in cell lysates were separated by SDS-PAGE and transferred to Odyssey nitrocellulose membranes (Licor) using the iblot® dry blotting transfer system (ThermoFisher). Nonspecific binding was blocked by incubating the membrane with Intercept Blocking Buffer (Licor) for 1 hour at room temperature with gentle shaking. The membrane was then incubated overnight at 4°C with primary antibodies rabbit anti-ER (Cell Signaling, 8644) and mouse anti-GAPDH (1:5,000, Santa Cruz Biotechnology, sc-47724) diluted in Intercept Blocking Buffer containing 0.1% Tween 20. After washing three times with TBS-T, the membrane was incubated with IRDye® 800CW goat anti-mouse IgG (1:20,000, Licor) or IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor) for 1 hour. After TBS-T washes, the membrane was rinsed in TBS and scanned with an Odyssey® CLx Imaging System (Licor). Bands were quantified using Image Studio™ software (Licor).

[0145] Figures 1A-1D show the ERα degradation activity of exemplary compounds 85, 60, 32, and 52 of the present disclosure in T47D cell line 6 hours after administration. Figures 2A and 2B show the ERα degradation activity of exemplary compounds 87 and 84 of the present disclosure in T47D cell line 6 hours after administration. Figures 4A and 4B show the ERα degradation activity of exemplary compounds 86 and 33 of the present disclosure in T47D cell line 6 hours after administration. Figures 6A-6C show the ERα degradation activity of exemplary compounds 41, 42, and 63 of the present disclosure in T47D cell line 6 hours after administration. Figures 7A-7D show the ERα degradation activity of exemplary compounds 89, 56, 90, and 74 of the present disclosure in T47D cell line 6 hours after administration.

[0146] Table 3 shows the ERα degradation activity of exemplary compounds of the disclosure in the T47D cell line 6 hours after administration. [Table 3]

[0147] 3A and 3B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in MCF7 cell lines 6 hours after administration.

[0148] 5A and 5B show the ERα degradation activity of exemplary compounds of the present disclosure, 86 and 33, in the CAMA1 cell line 6 hours after administration.

[0149] Since the many features and advantages of the present disclosure are apparent from the detailed specification, it is intended by the appended claims to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Moreover, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation illustrated and described, and therefore, all suitable modifications and equivalents may be deemed to fall within the scope of the present disclosure.

[0150] Moreover, those skilled in the art will appreciate that the conception underlying this disclosure may be readily utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present disclosure, and therefore the claims should not be deemed to be limited by the above description or examples. In one embodiment, for example, the following items are provided: (Item 1) Compounds of formula (I): [ka] or a stereoisomer or a mixture of stereoisomers, a pharma- ceutically acceptable salt, or a hydrate thereof, wherein R 1 is H or C 1 ~C 6 alkyl, each of which is selected from 0, 1, 2 or 3 R 6 is replaced by; R 2 and R 3 are independently H, C 1 ~C 3 Alkyl, or C 1 ~C 3 haloalkyl, each of which is selected from 0, 1, 2 or 3 R 6 is replaced by; Each R 4 is H, hydroxyl, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxyl, or C 1 ~C 3 haloalkyl, each of which is independently selected from 0, 1, 2 or 3 R 6 or two R 4 The groups together form oxo; R 5 is halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, -N(R 7 ) 2 , and -CN, each of which is selected from 0, 1, 2, or 3 R 6 is replaced by; X1 and X 2 are each independently H, halogen, cyano, or C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 haloalkyl, each of which is selected from 0, 1, 2 or 3 R 6 is replaced by; X 3 and X 4 are each independently selected from H or halo; L is a linker 1-22 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 is replaced by; Each R 6 is C 1 ~C 6 independently selected from alkyl, halo, cyano, and hydroxy; Each R 7 is hydrogen, C 1 ~C 6 alkyl, and acyl, each of which is independently selected from 0, 1, 2, or 3 R 6 or two R 7 The compounds, stereoisomers or mixtures of stereoisomers, pharma- ceutically acceptable salts, or hydrates thereof, wherein the groups taken together form a 3-6 membered heterocycle or heteroaryl. (Item 2) R 1 But H or C 1 ~C 6 alkyl, each of which is selected from 0, 1, 2 or 3 R 6 2. The compound according to item 1, or a pharma- ceutically acceptable salt thereof, wherein (Item 3) R 1 is selected from H or methyl, each of which is selected from 0, 1, 2 or 3 R 6 3. The compound according to item 2, or a pharma- ceutically acceptable salt thereof, wherein (Item 4) R 1 is selected from H or methyl, or a pharma- ceutically acceptable salt thereof. (Item 5) R 1 or a pharma- ceutically acceptable salt thereof. (Item 6) R1 5. The compound according to any one of items 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is methyl. (Item 7) R 2 and R 3 However, independently, H, C 1 ~C 3 Alkyl, or C 1 ~C 3 haloalkyl, each of which is selected from 0, 1, 2 or 3 R 6 7. The compound according to any one of items 1 to 6, or a pharma- ceutically acceptable salt thereof, substituted with: (Item 8) R 2 and R 3 are each independently selected from H and methyl, each of which is selected from 0, 1, 2 or 3 R 6 8. The compound according to any one of items 1 to 7, or a pharma- ceutically acceptable salt thereof, substituted with: (Item 9) R 2 and R 3 is each independently selected from H and methyl, or a pharma- ceutically acceptable salt thereof. (Item 10) R 2 and R 3 and R are each H; or a pharma- ceutically acceptable salt thereof. (Item 11) R 2 and R 3 and R are each methyl; or a pharma- ceutically acceptable salt thereof. (Item 12) R 2 and R 3 are H and methyl, respectively, or a pharma- ceutically acceptable salt thereof. (Item 13) Each R 4 H, hydroxyl, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxyl, or C 1 ~C 3 haloalkyl, each of which is independently selected from 0, 1, 2 or 3 R 6 or two R 4 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein the groups taken together form oxo. (Item 14) Each R 4 H, hydroxyl, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxyl, or C 1 ~C 3 haloalkyl, or two R 4 14. The compound according to any one of items 1 to 13, wherein the groups taken together form oxo, or a pharma- ceutically acceptable salt thereof. (Item 15) R 4 15. The compound according to any one of items 1 to 14, wherein is H, or a pharma- ceutically acceptable salt thereof. (Item 16) 2 R's 4 15. The compound according to any one of items 1 to 14, wherein the groups taken together form oxo, or a pharma- ceutically acceptable salt thereof. (Item 17) R 5 But halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, -N(R 7 ) 2 , and -CN, each of which is selected from 0, 1, 2, or 3 R 6 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt thereof, substituted with: (Item 18) R 5 But halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, -N(R 7 ) 2 18. The compound according to any one of items 1 to 17, wherein the compound is selected from -CN, or a pharma- ceutically acceptable salt thereof. (Item 19) R 5 19. The compound according to any one of items 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein is selected from halogen. (Item 20) R 5 20. The compound according to any one of items 1 to 19, wherein is F, or a pharma- ceutically acceptable salt thereof. (Item 21) X 1 and X 2 are each independently H, halogen, cyano, or C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 haloalkyl, each of which is selected from 0, 1, 2 or 3 R 6 21. The compound according to any one of items 1 to 20, or a pharma- ceutically acceptable salt thereof, substituted with: (Item 22) X 1 and X 2 are each independently H, halogen, cyano, or C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 22. The compound according to any one of items 1 to 21, or a pharma- ceutically acceptable salt thereof, selected from haloalkyl. (Item 23) X 1 and X 2 are each independently selected from H, F, CN, methyl, methoxy, trifluoromethyl, or a pharma- ceutically acceptable salt thereof. (Item 24) X 1 and X 2 and R are each H; or a pharma- ceutically acceptable salt thereof. (Item 25) X 1 and X 2 and R are each F; or a pharma- ceutically acceptable salt thereof. (Item 26) X 1 and X 2 are H and methyl, respectively, or a pharma- ceutically acceptable salt thereof. (Item 27) X 1 and X 2 are H and F, respectively, or a pharma- ceutically acceptable salt thereof. (Item 28) X 1 and X 2 are H and methoxy, respectively; or a pharma- ceutically acceptable salt thereof. (Item 29) X 1 and X 2 are F and methyl, respectively, or a pharma- ceutically acceptable salt thereof. (Item 30) X 1 and X 2 are F and methoxy, respectively; or a pharma- ceutically acceptable salt thereof. (Item 31) X 1 and X 2 are F and trifluoromethyl, respectively, or a pharma- ceutically acceptable salt thereof. (Item 32) X 3 and X 4 are each independently selected from H or halo, or a pharma- ceutically acceptable salt thereof. (Item 33) X 3 and X 4 are each independently selected from H or F, or a pharma- ceutically acceptable salt thereof. (Item 34) X 3 and X 4 and R are each H; or a pharma- ceutically acceptable salt thereof. (Item 35) X 3 and X 4 and R are each F; or a pharma- ceutically acceptable salt thereof. (Item 36) X 3 and X 4 are H and F, respectively, or a pharma- ceutically acceptable salt thereof. (Item 37) L is a linker 1 to 22 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 37. The compound according to any one of items 1 to 36, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 38) L is a linker 1 to 20 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R6 38. The compound according to any one of items 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 39) L is a linker 1 to 18 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 39. The compound according to any one of items 1 to 38, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 40) L is a linker 1 to 16 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 40. The compound according to any one of items 1 to 39, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 41) L is a linker 1 to 14 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 41. The compound according to any one of items 1 to 40, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 42) L is a linker 1 to 12 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 42. The compound according to any one of items 1 to 41, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 43) L is a linker 1-10 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 43. The compound according to any one of items 1 to 42, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 44) L is a linker of 1 to 8 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 44. The compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 45) L is a linker 1 to 8 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 45. The compound according to any one of items 1 to 44, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 46) L is a linker 1 to 6 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 46. ​​The compound according to any one of items 1 to 45, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 47) L is a linker 1 to 4 carbon atoms in length, where one or more of the carbon atoms is selected from the group consisting of C(O), O, NR 7 , S, C 2 -Alkenyl, C 2 - each optionally independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is represented by 0, 1, 2, or 3 R 6 47. The compound according to any one of items 1 to 46, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 48) L is a linker in which two carbon atoms are each independently replaced by a heterocycle, each of which is selected from 0, 1, 2, or 3 R 6 48. The compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 49) L is a linker, one carbon atom is replaced by a heterocycle, one carbon atom is replaced by a cycloalkyl, each of which is selected from 0, 1, 2, or 3 R 6 48. The compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt thereof, wherein each of the compound and the pharma- ceutically acceptable salt is independently substituted with: (Item 50) L is a linker and one or more of the carbon atoms is selected from C(O), O, NR 4 , S, C 2 -Alkenyl, C 2 - each independently substituted by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from 0, 1, 2, or 3 R 6 48. The compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt thereof, substituted with: (Item 51) L is a linker and one or more of the carbon atoms are selected from the group consisting of C(O), O, and NR 4 each of which is independently substituted by a group selected from 0, 1, 2 or 3 R 6 48. The compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt thereof, substituted with: (Item 52) L

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Claims

1. A compound or a pharma- ceutically acceptable salt thereof, said compound comprising: cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein the compound is (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of claim 1, wherein the compound is (S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharma- ceutically acceptable salt thereof.

4. 2. The compound of claim 1, wherein the compound is (S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a pharma- ceutically acceptable salt thereof.

5. 2. The compound of claim 1, wherein the compound is (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a pharma- ceutically acceptable salt thereof.

6. 10. A composition comprising a compound according to claim 2 for use in treating cancer in a subject in need thereof, wherein the cancer is breast cancer.

7. 4. A composition comprising a compound according to claim 3 for use in treating cancer in a subject in need thereof, wherein the cancer is breast cancer.

8. 10. A composition comprising a compound according to claim 4 for use in treating cancer in a subject in need thereof, wherein the cancer is breast cancer.

9. 10. A composition comprising a compound according to claim 5 for use in treating cancer in a subject in need thereof, wherein the cancer is breast cancer.

10. 10. A composition comprising a compound according to claim 2 for use in treating cancer in a subject in need thereof, wherein the cancer is ovarian cancer.

11. 4. A composition comprising a compound according to claim 3 for use in treating cancer in a subject in need thereof, wherein the cancer is ovarian cancer.

12. 10. A composition comprising a compound according to claim 4 for use in treating cancer in a subject in need thereof, wherein the cancer is ovarian cancer.

13. 10. A composition comprising a compound according to claim 5 for use in treating cancer in a subject in need thereof, wherein the cancer is ovarian cancer.

14. 10. A composition comprising a compound according to claim 2 for use in treating cancer in a subject in need thereof, wherein the cancer is endometrial cancer.

15. 4. A composition comprising a compound according to claim 3 for use in treating cancer in a subject in need thereof, wherein the cancer is endometrial cancer.

16. 10. A composition comprising a compound according to claim 4 for use in treating cancer in a subject in need thereof, wherein the cancer is endometrial cancer.

17. 10. A composition comprising a compound according to claim 5 for use in treating cancer in a subject in need thereof, wherein the cancer is endometrial cancer.

18. 13. A composition comprising a compound of claim 1 for treating cancer in a subject in need thereof, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

19. 13. A composition comprising a compound of claim 1 for treating a disease or condition in a subject in need thereof, wherein the disease or condition is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, esophageal cancer, infertility, ovulatory dysfunction, postmenopausal osteoporosis, estrogen-associated gynecomastia, dyspareunia due to menopause, retroperitoneal fibrosis, and idiopathic sclerosing mesenteritis.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and at least one additional component selected from a pharma- ceutically acceptable carrier, a pharma- ceutically acceptable vehicle, and a pharma- ceutically acceptable excipient.

21. 23. Use of a compound of claim 1 or a pharmaceutical composition of claim 20 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

22. 22. The use of claim 21, wherein the cancer is ERα positive.

23. 22. The use of claim 21, wherein the subject has previously been treated with an anti-cancer agent.

24. 24. The use of claim 23, wherein the anticancer drug is tamoxifen or fulvestrant.

25. 13. Use of a compound of claim 1 in the manufacture of a medicament for treating a disease or condition in a subject in need thereof, wherein the disease or condition is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, esophageal cancer, infertility, ovulatory dysfunction, postmenopausal osteoporosis, estrogen-associated gynecomastia, dyspareunia due to menopause, retroperitoneal fibrosis, and idiopathic sclerosing mesenteritis.

26. 21. The pharmaceutical composition of claim 20 for treating cancer in a subject in need thereof, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

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